Mucinous rectal adenocarcinoma and neoadjuvant therapy: Implications for surgical practice

Abstract

Mucinous adenocarcinoma (MAC) of the rectum is characterized by ≥ 50% extracellular mucin, constitutes 5%-20% of rectal cancers, and exhibits distinct biological and clinical behaviors compared to non-MAC. Accumulating evidence indicates that MAC may cause reduced responsiveness to standard chemoradiotherapy with notably lower rates of pathologic complete response and tumor downstaging. Meta-analyses report an odds ratio of 0.38 for pathologic complete response in MAC relative to non-MAC. In recent years total neoadjuvant therapy (TNT) has emerged as the preferred preoperative approach for locally advanced rectal cancer, integrating systemic chemotherapy and chemoradiation before surgical intervention. Likely, TNT may be insufficient to fully overcome MAC resistance, but conclusive data are lacking. MAC tumors tend to be larger, possess poorly defined planes, increase the risk of circumferential resection margin positivity, and are infrequently suitable for organ-preserving strategies such as watch-and-wait. All these aspects have direct implications for surgical practice. This review consolidated current evidence concerning the response of MAC to TNT, delineated surgical challenges, and emphasized priorities for multidisciplinary care and research.

Key Words: Rectal cancer; Mucinous adenocarcinoma; Total mesorectal excision; Surgery; Total neoadjuvant therapy; Radiotherapy; Multivisceral resection; Watch-and-wait

Core Tip: Mucinous adenocarcinoma (MAC) is a distinct histologic subtype characterized by abundant extracellular mucin and a reduced response to neoadjuvant chemoradiotherapy or total neoadjuvant therapy. This review integrated molecular, radiologic, and surgical evidence to explain why MAC behaves differently and how meticulous total mesorectal excision can mitigate these challenges. When tumor downstaging and complete (R0) resection are achieved after total neoadjuvant therapy, long-term outcomes may be comparable to non-MAC, underscoring the importance of surgical precision and multidisciplinary planning.

INTRODUCTION

Mucinous adenocarcinoma (MAC) of the rectum is histologically characterized by abundant extracellular mucin comprising at least 50% of the tumor volume. It accounts for 5%-20% of rectal cancers with a higher prevalence observed in Western countries and lower rates reported in Asian series. Beyond its histologic classification MAC is increasingly recognized as a biologically and clinically distinct entity with significant implications for oncologic treatment and surgical management[1-5].

Recent studies have elucidated the clinicopathologic profile of MAC. Patients with MAC frequently tend to present at more advanced stages (T3-T4), and the tumors often exhibit poor differentiation, lymph vascular invasion, and peritoneal spread rather than the classic liver-predominant metastases seen in non-MAC (NMAC)[6]. Lan et al[7] demonstrated that MAC was associated with distinct metastatic patterns and more aggressive local behavior, particularly in cases of left-sided and rectal tumors, which frequently recur locally or on the peritoneum rather than in the liver.

At a molecular level MAC also shows a unique genetic and transcriptomic signature. It is more frequently associated with microsatellite instability (MSI), lower TP53 mutation rates[8], and alterations in the AKT1 and TGFβ pathways, suggesting differences in tumor biology that influence both prognosis and therapeutic responsiveness[9]. Even more strikingly, MAC expresses higher levels of chemotherapy resistance genes involved in 5-fluoroucil and oxaliplatin metabolism, including TYMS, TYMP, and DYPD[4,10].

This differential expression profile provides a biological rationale for the common observation that MAC often exhibits reduced responsiveness to conventional neoadjuvant therapy protocols that rely on fluoropyrimidine and oxaliplatin regimens. These insights outline the main issues faced by colorectal surgeons and multidisciplinary teams. MAC may show a less effective response to standard neoadjuvant chemoradiotherapy with reductions in response extensively documented in the scholarly literature[10-14]. These biological distinctions pose concrete technical challenges during surgical procedures, impacting dissection planes, margin security, and operative strategies. Surgical timing, planning, and eligibility criteria for organ-preserving approaches must be reconsidered in light of the distinctive characteristics of MAC[11].

Although MAC typically exhibits a more aggressive phenotype and demonstrates a reduced response to neoadjuvant therapy, numerous studies have indicated that patients who undergo tumor downstaging and achieve a complete (R0) resection can attain long-term survival rates comparable with those with NMAC. This evidence underscores the importance of radical surgical intervention in improving overall survival (OS) in this context.

Future research priorities should focus on determining whether novel treatment strategies, such as total neoadjuvant therapy (TNT) protocols, can mitigate the adverse clinical effects associated with MAC status, identifying molecular targets, and incorporating innovative therapeutics to improve outcomes for this particularly challenging subgroup. The following sections systematically address these themes. First, we reviewed the evidence concerning the response of MAC to neoadjuvant therapy. Subsequently, we examined data on TNT in MAC, emphasizing the limitations and gaps. These findings were then translated into practical implications for surgeons, including operative planning, margin management, and organ preservation decisions. Finally, we discussed multidisciplinary considerations and outlined future research directions, including molecularly targeted strategies that may transform the therapeutic landscape for MAC.

METHODOLOGY

A comprehensive literature review was conducted utilizing the PubMed database to identify studies published from January 2000 to August 2025. The search strategy combined the terms “mucinous adenocarcinoma,” “rectal cancer,” “neoadjuvant chemoradiotherapy,” “total neoadjuvant therapy,” “preoperative treatment,” and “surgery” using appropriate Boolean operators. Only English-language publications were included.

The search yielded 184 records. After screening titles and abstracts, 114 articles were excluded because they were unrelated to rectal MAC, did not investigate preoperative chemoradiotherapy or TNT, or lacked surgical relevance. The remaining 70 studies underwent full-text review. Of these, 24 were excluded due to small case series or single case reports (n = 10), non-English publications (n = 5), and studies with insufficient or non-extractable oncological or surgical outcome data (n = 9). Ultimately, 46 studies were included in the qualitative synthesis. Eligible publications encompassed systematic reviews, meta-analyses, randomized controlled trials, large registry-based cohorts, and high-quality retrospective series addressing MAC treated with neoadjuvant chemoradiotherapy or TNT followed by surgery.

Extracted data included clinicopathological characteristics, molecular and imaging findings, rates of tumor and nodal downstaging, pathologic complete response (pCR), circumferential resection margin (CRM) status, and the need for extended or multivisceral resection. Long-term outcomes such as recurrence pattern, disease-free survival (DFS), and OS were also collected. Quantitative parameters including odds ratios, hazard ratios (HRs), and confidence intervals were recorded when available. Given the heterogeneity of study designs and endpoints, the data were synthesized narratively. This approach allowed the integration of multidisciplinary evidence from molecular and imaging studies to clinical and surgical analyses to provide a comprehensive and clinically meaningful interpretation of the management and outcomes of rectal MAC.

Beyond clinical and surgical research, the search strategy also incorporated terms associated with “cost,” “resource utilization,” and “health economics” to encompass relevant evidence regarding the financial burden of complex surgical procedures necessary for MAC treatment and postoperative monitoring.

The methodological quality of this narrative review was assessed using the Scale for the Assessment of Narrative Review Article criteria achieving a total score of 12/12 indicated excellent adherence to standards of methodological rigor, transparency, and interpretative balance (Figure 1)[15].

Figure 1 Article selection flow diagram. The selection of studies included in the narrative review. From 184 records initially identified, 46 met the inclusion criteria, 44 clinical and surgical studies forming the main synthesis plus 2 additional articles separately addressing cost and resource utilization in mucinous adenocarcinoma (MAC) management. SANRA: Scale for the Assessment of Narrative Review Articles; TNT: Total neoadjuvant therapy.

EVIDENCE ON NEOADJUVANT THERAPY EFFECTS IN MAC

An increasing body of evidence confirms that rectal MAC exhibits a markedly reduced response to standard neoadjuvant chemoradiotherapy when compared with NMAC (Table 1). Multiple systematic reviews and meta-analyses have consolidated findings across large datasets, consistently reporting significantly lower rates of tumor regression, pCR, and downstaging in MAC[10,12-14,16-19]. A recent high-quality meta-analysis synthesizing data from 15 studies involving more than 9000 patients reported that mucinous histology was associated with an odds ratio of 0.38 for achieving a pCR and 0.31 for tumor downstaging relative to non-mucinous histology, indicating that the biological characteristics of MAC confer some form of resistance to neoadjuvant therapy. Nodal downstaging was less consistently observed with some studies noting a numerical but not statistically significant reduction[22].

Table 1 Evidence on the neoadjuvant response in mucinous rectal adenocarcinoma.

Ref.	Design	Population	Key findings
Huang et al[3], 2021	Meta-analysis (15 studies)	> 9000 patients	MAC associated with OR 0.38 for pCR and 0.31 for tumor downstaging vs non-MAC
Zhang et al[18], 2021	Pooled analysis of 3 prospective trials	743 patients (8.5% MAC)	pCR: 7.5% in MAC vs 22.0% non-MAC; yp stage 0-I: 20.8% vs 48.7%; DFS 3-year: 58.4% vs 77.6%
McCawley et al[23], 2016	Meta-analysis	Multiple datasets	Higher CRM positivity (OR 5.02) and mortality (OR 1.53) in MAC
Yu et al[56], 2014	MRI-based prognostic study	Retrospective cohort	Poor radiologic regression; acellular mucin mimics residual tumor on MRI

Summary of key studies evaluating the pathological complete response (pCR), tumor downstaging, margin status, and imaging findings in mucinous adenocarcinoma (MAC) compared with non-MAC. Data highlighted consistent reductions in pCR and downstaging rates for MAC, higher rates of circumferential resection margin (CRM) involvement, and challenges in radiologic assessment due to acellular mucin mimicking residual tumor. DFS: Disease-free survival; MRI: Magnetic resonance imaging; OR: Odd ratio.

Individual patient data analyses offer additional granularity. A pooled analysis of three prospective trials involving 743 patients, among whom 8.5% exhibited mucinous histology, revealed a pCR rate of only 7.5% in MAC compared with 22.0% in NMAC. Tumor downstaging to yp stage 0-I was achieved in 20.8% of MAC cases vs 48.7% of NMAC cases. Notably, this diminished responsiveness correlated with poorer long-term outcomes with 3-year DFS rates of 58.4% in patients with MAC vs 77.6% in those with NMAC histology, and a locoregional recurrence rate of 26.0% compared with 5.7%. Multivariable analysis identified mucinous histology as an independent predictor of inferior DFS[18].

Additional evidence from McCawley et al[23] further supports the assertion that mucinous histology predicts poorer oncologic outcomes extending beyond response rates. Their meta-analysis confirmed that MACs were associated with markedly increased odds of circumferential margin involvement (odds ratio 5.02) and an overall increase in mortality risk (odds ratio 1.53), indicating that both biological behavior and treatment resistance contribute to suboptimal outcomes. Furthermore, other observational series have reported pCR rates approaching zero within specific mucinous cohorts, underscoring the degree of resistance inherent to this histologic subtype[23].

TNT IN MAC

TNT for locally advanced rectal cancer involves administering both radiation and systemic chemotherapy prior to surgical intervention as opposed to the conventional approach of neoadjuvant chemoradiotherapy administered solely before surgery or adjuvant therapy provided postoperatively. This strategy aims to enhance control of distant metastases, improve DFS, and potentially increase the rates of significant tumor responses, thereby facilitating surgical management in numerous cases[17]. Four randomized phase III trials have examined the role of TNT with their primary characteristics summarized in Table 2. Although TNT has demonstrated promising outcomes, particularly in trials such as RAPIDO and PRODIGE 23, ongoing research is directed towards identifying optimal TNT regimens and determining patient populations that stand to benefit most from this intensive therapeutic approach[24,25].

Table 2 Comparison of the four trials using total neoadjuvant therapy in the study arm.

Study name	Primary endpoints	TNT arm	Control arm	pCR (%) study	pCR (%) control	DFS (months) study	DFS (months) control
PRODIGE23	3-year DFS	CTX/CRT/TME	CRT/TME	28	12	76	69
RAPIDO	3-year DRTF	SCRT/CTX/TME	CTX/CRT/TME	28	14	23.7	30.4
OPRA	DFS	CTX/CRT/TME	CRT/CTX/TME	NA	NA	76	76
STELLAR	DFS	SCRT/CTX/TME	CRT/TME	17.2	13.9	64.3	62.3

CRT: Long-course chemoradiotherapy; CTX: Chemotherapy; DFS: Disease-free survival; DRTF: Disease-related treatment failure; NA: Not available; pCR: Pathologic complete response; SCRT: Short-course radiotherapy; TME: Total mesorectal excision; TNT: Total neoadjuvant therapy.

Regarding MAC tumors, there is a significant lack of specific data on tumor response rates, pCRs, and survival analyses across these four clinical trials (Table 2)[24,26-28]. MAC appears to constitute an unfavorable histologic trait in cases of locally advanced rectal cancer treated with standard chemoradiation, thereby negatively influencing treatment outcomes. Nevertheless, this observation should not be automatically generalized to other therapeutic protocols and strategies, such as TNT. MAC tumors are frequently poorly differentiated with approximately 70%-80% of instances occurring in the middle and lower thirds of the rectum. Consequently, these characteristics may serve as a surrogate indicator for the presence of MAC tumors.

An increased prevalence of MAC histology in rectal cancer may contribute to poorer prognoses for mid and upper rectal cancers as evidenced by lower 5-year OS rates (approximately 45%-50%) and DFS rates (approximately 40%-50%) compared with 65%-75% in mid and upper rectal cancers. In the PRODIGE, RAPIDO, and STELLAR trials (Table 2)[24,26,28], the location of the tumor inferiorly suggested a trend toward reduced DFS. To examine the potential clinical impact of MAC histology, comprehensive retrospective analyses within randomized TNT trials should be undertaken to evaluate the predictive and prognostic significance of MAC. Currently, patients exhibiting histologic features of MAC should be treated in accordance with established guidelines, including TNT. Once it is confirmed that MAC adversely affects clinical outcomes in patients undergoing TNT, intensified treatment regimens or innovative combinations, such as immunotherapy for MSI-high MAC, will emerge as focal points in ongoing research.

RADIOLOGY ASSESSMENT OF TUMOR RESPONSE

MAC displays characteristic imaging features that distinguish it from NMAC. On high-resolution magnetic resonance imaging (MRI), mucinous tumors show markedly hyperintense T2-weighted signal with a heterogeneous, often multilobulated appearance and peripheral or septal enhancement on post-contrast sequences, reflecting pools of extracellular mucin and sparse viable tumor cellularity (Figure 2)[29,30]. Diffusion-weighted imaging typically demonstrates low restricted diffusion due to the low cellular density of mucin, resulting in higher apparent diffusion coefficient (ADC) values compared with those observed in NMAC.

Figure 2 Pretreatment magnetic resonance imaging of a patient with mucinous adenocarcinoma. A: Sagittal T2-weighted image showed a bulky, multilobulated rectal mass with markedly high signal intensity due to abundant extracellular mucin, extending toward the mesorectal fascia; B: Axial T2-weighted image demonstrated the same lesion with homogeneous hyperintense signal and poorly defined borders against the mesorectal fat, typical of mucinous tumors. These imaging features, high T2 signal, gelatinous internal texture, and ill-defined margins, are characteristic of mucinous histology and help differentiate mucinous adenocarcinoma from non-mucinous rectal adenocarcinoma.

Positron emission tomography (PET)/MRI and PET/CT further emphasize the metabolic contrast: Tumors containing mucinous components display significantly lower glucose uptake (SUVmax 7.4 vs 16.7, P = 0.002) despite being associated with a higher T category (≥ T3c in 88% of cases) and frequent extramural vascular invasion[30]. These metabolic and morphologic characteristics elucidate why MACs often presents as bulky, poorly defined tumors with more frequent involvement of the mesorectal fascia and extramural vascular invasion, findings corroborated by Enblad et al[31] in a population-based Swedish registry in which 51% had positive mesorectal fascia and 44% exhibited extramural vascular invasion on MRI[31].

Lymph node assessment also presents specific challenges. MAC frequently exhibits mucin-containing or cystic nodal metastases, which may not display restricted diffusion or glucose avidity, consequently resulting in false negative nodal staging on standard imaging[30]. Consequently, MRI and PET criteria optimized for non-mucinous disease may underestimate the N stage in MAC. Following neoadjuvant chemoradiotherapy or TNT, restaging MRI in MAC remains one of the most challenging aspects of disease evaluation. Persistent T2 hyperintensity within the treated area frequently represents acellular mucin (AM) rather than viable carcinoma. In a multicenter analysis Koëter et al[14] reported that mucinous rectal cancers often show poor radiologic regression despite pathologic response, and MRI overstaged disease in up to 40% of cases. Miranda et al[19] confirmed that post-treatment mucinous degeneration can be observed in up to 25% of rectal cancers and is not consistently associated with poor prognosis.

Importantly, Judge et al[32] demonstrated that residual mucin on MRI does not contraindicate a watch-and-wait (W&W) approach. In their 2024 series from Memorial Sloan Kettering, 79% of patients with residual mucin but a complete clinical response remained disease-free at 50 months with regrowth salvageable surgically. Advanced imaging techniques can assist in differentiating viable tumors from acellular tissue mucin. Quantitative diffusion metrics, such as ADC and T2-mapping, can detect residual tumor nodules characterized by lower ADC and intermediate T2 values. Radiomics has demonstrated significant utility in distinguishing residual tumors from AM, attaining diagnostic accuracies exceeding 80%. However, precise interpretation continues to necessitate the expertise of a well-trained radiologist as human judgment remains indispensable for contextualizing radiomic findings within the intricate post-treatment morphology of mucinous rectal tissue cancer[16,33,34]. Accurate imaging is essential for the detection of local recurrence MAC, as recurrent disease frequently mimics postoperative or post-radiation changes (Figure 3).

Figure 3 Pelvic magnetic resonance imaging revealed a local recurrence of mucinous adenocarcinoma 4 years subsequent to an R0 abdominoperineal resection. Sagittal T2-weighted image demonstrated a lobulated, high-signal-intensity mass in the presacral space, consistent with recurrent mucinous disease. The lesion exhibited homogeneous T2 hyperintensity typical of extracellular mucin and ill-defined margins against adjacent pelvic structures. These imaging features are characteristic of mucinous local recurrence and help differentiate it from postoperative seroma or fibrosis.

On MRI local recurrence typically appears as a lobulated or irregular T2-hyperintense mass with variable enhancement and mild diffusion restriction, whereas benign postoperative collections usually show smooth margins, homogeneous fluid signal, and no solid or enhancing components[29-31]. The distinction can be difficult because AM or sterile fluid collections may have a similar T2 appearance; however, restricted diffusion, nodular enhancement, or progressive increase in size on serial imaging favor recurrence over postoperative fluid or fibrosis. Due to the low cellularity of mucin, glucose uptake on PET/CT or PET/MRI is often low, potentially causing false-negative results. Therefore, combining morphologic MRI, diffusion-weighted imaging, and metabolic assessment improves diagnostic accuracy with PET/MRI offering the highest specificity for differentiating true recurrence from postoperative changes or sterile mucin deposits[16]. Therefore, structured imaging follow-up, particularly in patients managed with organ preservation or a W&W approach, is crucial as early identification of local regrowth enables prompt salvage surgery with curative intent.

SURGICAL IMPLICATIONS

Pathologic response and organ preservation

Due to the inferior results of neoadjuvant therapy in MAC, strategies such as extending the interval between neoadjuvant treatment and surgery have been examined. A large meta-analysis involving over 25000 patients showed that waiting at least 8 weeks (compared to the traditional 6-8 weeks) after chemoradiotherapy significantly increased pCR rates (approximately 1.4 times higher odds) without increasing surgical complication rates[35]. Because MAC is less likely to fully respond, organ preservation through non-operative management is achieved in fewer cases. Nonetheless, outcomes from W&W cohorts in which surgery was omitted after a clinical complete response suggest that if a patient with MAC achieves a complete clinical response, careful observation can be feasible. Overall, the W&W series, mostly involving NMAC cases, report local tumor regrowth in approximately 20%-30% of patients within 2-3 years, but salvage surgery is usually successful. Local recurrence was significantly higher with W&W than upfront surgery (relative risk = 6, P < 0. 001). Nevertheless, 78.4% of regrowths were amenable to salvage resection with a 97.5% R0 resection rate on salvage. Significantly, long-term survival rates were comparable between the W&W approach and upfront surgery in patients exhibiting complete responses as the immediate salvage of local failures effectively mitigated any potential disadvantages in OS[36]. These findings emphasize that organ preservation is oncologically safe on the condition that rigorous surveillance is maintained.

Operative planning and surgical technique

MAC presents unique surgical challenges; in fact, it is frequently characterized by large lesions. MAC has an odds ratio of approximately 2.26 for presentation with tumors ≥ 5 cm compared with smaller tumors and is also associated with a more advanced T stage at diagnosis (Table 3)[7,9]. Consequently, cases of MAC often require more aggressive surgical interventions. Achieving clear CRM is more challenging as MAC tends to invade adjacent tissues[37]. A propensity-matched analysis demonstrated that following neoadjuvant therapy and total mesorectal excision positive radial margins were observed in 29% of MAC cases compared with 15% of NMAC cases (nearly double the incidence despite comparable treatments)[38]. Notably, even in series limited to multivisceral resections, the likelihood of a positive resection margin remains high with a R0 resection rate of only 72% despite extended surgery. This outcome was, in turn, associated with higher recurrence rates and poorer survival[37]. Therefore, mucinous histology is recognized as a significant risk factor for margin involvement and non-radical resection.

Table 3 Impact of mucinous histology on surgical complexity and outcomes.

Ref.	Surgical parameter	MAC	Non-MAC
Hugen et al[2], 2014; Lan et al[7], 2021	Mean tumor size (cm)	5.2-6.8	3.5-4.5
McCawley et al[23], 2016; Hugen et al[2], 2014	CRM positivity rate (%)	14-28	6-11
Hugen et al[2], 2014; Lan et al[7], 2021	Rate of T4 disease at presentation (%)	26-33	10-17
Lohsiriwat and Lohsiriwat[41], 2008; de Nes et al[39], 2021	Multivisceral resection requirement (%)	12-18	4-7
Lohsiriwat and Lohsiriwat[41], 2008	Mean operative time for extended resections (minute)	274 ± 73	157 ± 62
Lohsiriwat and Lohsiriwat[41], 2008	Median blood loss for extended resections (mL)	769 ± 549	203 ± 136
Pelvex Collaborative[40], 2019	Major complication rate (Clavien-Dindo ≥ III, %)	38%	NA
Pelvex Collaborative[40], 2019; Hendrick et al[38], 2025	R0 resection rate in extended resections (%)	~ 72	~ 88

Summary of comparative surgical parameters for mucinous adenocarcinoma (MAC) and non-MAC. Data include tumor size, frequency of T4 disease, rates of circumferential resection margin (CRM) positivity, requirement for multivisceral resection, operative time, blood loss, complication rates, and R0 (no residual disease at surgery) resection rates in extended resections. Figures are derived from comparative observational series and meta-analyses within populations with locally advanced rectal cancer. NA: Not available.

Similarly, a prior meta-analysis reported a five-fold increased likelihood of positive resection margins in MAC[23]. These findings emphasize the necessity of meticulous preoperative planning. High-resolution MRI is especially crucial for MAC as it enables assessment of tumor extent and assists in planning for adequate mesorectal and extramesorectal clearance[33]. Since MAC may disseminate via mucin pools and invade the peritoneum, extended or multivisceral resections for T4 disease are often considered. Indeed, a complete total mesorectal excision or even extra-mesorectal dissection might be necessary to minimize residual disease[38]. When adjacent organs or structures are involved, en bloc multivisceral resection is recommended to achieve an R0 resection. The necessity for multivisceral resection in low rectal MAC has not been extensively quantified in large series; however, the higher T3/T4 rates suggest it is more common than in NMAC cases[39].

Of note, the selection of surgical technique significantly influences outcomes. MAC produces a slippery consistency, complicating minimally invasive procedures. The National Cancer Data Base study indicated a trend toward higher positive margin rates with laparoscopic or robotic approaches in MAC. CRM involvement was 35% with minimally invasive techniques compared with 26% with open surgery (P = 0.09). While not statistically definitive, this suggests that some MAC cases may benefit from an open or hybrid approach to enhance visualization and palpation. Conversely, conversion to an abdominoperineal resection for low tumors adheres to the same oncologic standards as in NMAC cases; histology alone does not preclude sphincter preservation if clear margins are attainable[38].

Despite the increased complexity, intraoperative and postoperative complication rates are not necessarily elevated when surgery is appropriately executed. Comparative studies have demonstrated that rates of anastomotic leak, pelvic sepsis, and stoma formation are comparable in patients with MAC and NMAC[35]. Nonetheless, cases requiring multivisceral resection or wider operative fields inherently involve higher morbidity. One series of extended resections for advanced rectal cancer reported complication rates exceeding 30%, reflecting the added intricacy[40]. Comparative data also show that partial/total pelvic exenteration entails longer operative time and greater blood loss than non-exenterative rectal resections even when short-term outcomes can remain acceptable in selected patients[41].

Pathologic findings: Differentiating AM from residual tumor

A hallmark of successfully treated MACs is the frequent observation of AM pools in resected specimens. Following neoadjuvant chemoradiotherapy, it is common to encounter lakes of mucin devoid of viable tumor cells, often described as “ghost” tumor material. Between 20%-40% of rectal cancers exhibit AM pools after neoadjuvant chemotherapy[42]. This phenomenon is especially prominent in MAC although tumors initially non-mucinous in nature may also develop therapy-induced mucin degeneration. The prognostic significance of AM has been extensively studied, particularly in cases where patients meet criteria for pCR. Evidence suggests that when only AM remains, meaning no viable tumor cells are detected, the patient’s prognosis aligns closely with those who achieve a true pCR. Similarly, lymph nodes that contain mucin pools but lack cancer cells are regarded as free of metastasis. Consequently, current guidelines acknowledge that a case with AM and no viable cancer cells in both the primary tumor and lymph nodes indicates a pCR (ypT0N0)[43].

In a study involving 117 patients wtih rectal cancer who attained pCR after neoadjuvant chemotherapy, 23% exhibited residual AM on pathology. Remarkably, their 5-year DFS (approximately 96%) and OS (approximately 100%) were statistically similar to those of patients with pCR, who had DFS of 83.7% and OS of 87.5%. Analyses showed that AM did not increase the risk of recurrence or compromise survival (HR for DFS was 0.22; P = 0.15), underlining that these mucin pools likely represent a favorable treatment responder rather than evidence of remaining active malignancy[42]. From a prognostic perspective the key distinction lies in the presence or absence of viable tumor cells. Any residual viable tumor in the specimen indicates an incomplete response, correlating with poorer oncologic outcomes[44]. Large meta-analyses consistently demonstrate that patients without pCR experience significantly higher rates of relapse and decreased survival. For instance, at 5 years the DFS for patients with pCR is approximately 87% compared with 50%-70% in those with residual tumor, indicating over a four-fold increased risk of recurrence if complete response is not achieved. Consequently, rigorous pathologic sampling of mucin-rich areas is essential to ensure no hidden microscopic tumor cells are overlooked[45,46].

Postoperative outcomes, recurrence patterns, and surveillance

Despite its adverse biological profile, MAC does not inevitably confer poorer long-term outcomes. In well-selected patients who achieve tumor downstaging after neoadjuvant chemoradiotherapy or TNT and undergo a meticulous R0 surgery, survival is comparable to that of NMAC (Table 4)[6]. A recent meta-analysis including 56 studies and over 800000 patients found a small but statistically significant reduction in OS for MAC (pooled HR = 1.04, P < 0.01) while DFS was virtually identical (HR = 1.01, P = 0.85)[6]. These findings highlight that it is the completeness of resection and stage at presentation rather than histology alone that drives prognosis.

Table 4 Postoperative outcomes and recurrence patterns in mucinous rectal tumors.

Ref.	Outcome	MAC	Non-MAC
Hugen et al[2], 2014; McCawley et al[23], 2016	3-year local recurrence rate (%)	14-26	4-8
Hugen et al[2], 2014; Lan et al[7], 2021	3-year disease-free survival (%)	58-64	76-82
Hugen et al[2], 2014; Lan et al[7], 2021	Common metastatic sites	Peritoneum, lung	Liver
McCawley et al[23], 2016; Hugen et al[2], 2014	Median time to recurrence (months)	13-16	18-21
Hugen et al[2], 2014	Recurrence with peritoneal carcinomatosis (%)	20-28	< 10

MAC: Mucinous adenocarcinoma.

Registry data for rectal cancer further confirm that when a surgery is performed to high technical standards, the 5-year OS for MAC (approximately 52%) approaches that of NMAC (approximately 59%)[12]. In fact, stage-specific analyses demonstrate nearly equivalent outcomes: Stage II MAC resembles stage II NMAC; and in some series stage III MAC even attains superior survival rates (88% vs 71%). This apparent survival advantage in stage III MAC may be partially explained by increased chemotherapy sensitivity or younger age at diagnosis as well as a selection effect since patients achieving downstaging and proceeding to curative resection represent a biologically favorable subset[47,48]. A well-executed R0 surgery, therefore, appears capable of offsetting the adverse biological behavior of MAC, reinforcing the central role of surgical precision in determining outcome. Conversely, incomplete resection or poor tumor regression remain the strongest predictors of pelvic regrowth[11,38,49].

Where mucinous histology shows a more striking impact is in patterns of distant spread. MAC exhibits a predilection for peritoneal metastases as opposed to the hematogenous routes more typical of NMAC. In a large single-institution study among patients who developed metastases, peritoneal metastasis occurred in 31.8% of MAC vs only 5.8% of NMAC (P < 0.001). Conversely, lung metastases were more common in patients with NMAC (in the same study, 39% of NMAC had lung metastases vs approximately 21% of MAC, P = 0.013). Liver metastasis rates were relatively similar with a slight trend toward higher incidence in NMAC[50]. These data align with clinical observations: MAC (especially in the colon) often spread diffusely in the abdominal cavity (sometimes as pseudomyxoma peritonei), whereas typical rectal adenocarcinomas more often spread to the liver and lungs. For rectal MAC, which is partly an intraperitoneal disease (upper rectum) and partly extraperitoneal (distal rectum), both paradigms are applicable. Therefore, meticulous monitoring is necessary for peritoneal carcinomatosis in addition to the typical metastatic sites. Indeed, the mucin itself is thought to facilitate cancer cell dissemination along peritoneal surfaces. One hypothesis is that pressurized mucin dissects tissue planes, allowing tumor cells to seed the peritoneum early. Regardless of mechanisms, clinicians should maintain a high index of suspicion for peritoneal relapse (e.g., unexplained ascites or omental caking on scans) in patients who survived MAC[3,50].

Follow-up recommendations for MAC largely mirror standard rectal cancer surveillance protocols albeit with certain differences. Although there are no separate official guidelines for mucinous histology, many experts advocate for more rigorous imaging surveillance due to the tendency for atypical metastatic patterns[47]. Typically, following curative resection of rectal cancer, patients undergo physical examinations, carcinoembryonic antigen testing, and CT scans of the chest, abdomen, and pelvis every 6-12 months over a 5-year period along with periodic colonoscopy[48]. For patients with MAC, imaging modalities such as CT or MRI are particularly crucial for detecting peritoneal or pelvic recurrence, which may not be visible on endoscopy[14,16,19,33]. Some clinicians may opt to conduct imaging at the more frequent end of the guideline range (e.g., every 6 months during the first 3 years) in instances of high-risk histology.

Literature indicates that patients with MAC require special consideration during follow-up. One reason is that routine surveillance colonoscopy is less effective in detecting mucinous recurrences, which often present as extraluminal nodules or ascites; therefore, cross-sectional imaging becomes essential[49]. Patients with MAC can be stratified for the risk of recurrence, helping to tailor surveillance protocols. To better stratify risk nomogram-based models have been developed specifically for rectal MAC.

A recent study utilized data from the SEER registry to develop a prognostic nomogram for cancer-specific survival following surgery in patients with rectal MAC. The model identified patient age and tumor-node-metastasis stage as the dominant predictors of outcome and achieved a reasonable concordance index (approximately 0.72) in the validation set. Such a tool can estimate 1-year, 3-year, and 5-year survival probabilities for an individual with rectal MAC, informing the intensity of surveillance[11]. For instance, a young patient with stage IIA MAC might have an excellent prognosis and follow standard surveillance, whereas an elderly patient with stage IIIC MAC is at much higher risk and could benefit from more aggressive monitoring. The nomogram highlighted the fact that stage drives prognosis. Indeed, the 5-year survival in that study ranged from approximately 90% in early-stage MAC to approximately 40%-50% in advanced-stage MAC, paralleling stage-matched expectations. In practical terms, clinicians should use all available risk factors (histology, tumor response, stage, etc.) to tailor an appropriate follow-up. At a minimum, regular imaging such as CT or MRI should be conducted.

ECONOMIC CONSIDERATIONS

The economic burden associated with the management of locally advanced rectal cancer with mucinous histology is significant, reflecting both the intensity of multimodal therapeutic interventions and the complexity of surgical procedures. Cost data derived from extensive exenterative series illustrate the considerable resource utilization related to radical pelvic surgery. In a contemporary Australian cohort comprising 461 patients, the median total inpatient cost of pelvic exenteration was AUD 108259 (interquartile range: AUD 86621 to AUD 144429) with staffing costs (35%) and operating room expenses (23%) representing the primary components of expenditure. Complete multivisceral resections when combined with cytoreductive surgery or hyperthermic intraperitoneal chemotherapy resulted in an increase in admission costs by an average of AUD 34000 and AUD 76000, respectively. Additionally, complications and prolonged hospital stays were independently associated with cost increases exceeding 50%[51]. These findings highlight that the main cost drivers are operative complexity and postoperative morbidity rather than oncologic factors like margin status. Concurrently, literature pertaining to oncologic surveillance indicates that the post-treatment phase also substantially contributes to overall healthcare expenditure. Rettenmaier et al[52] estimated a cumulative 16-year surveillance cost exceeding USD 2.4 million for 287 patients with gynecologic malignancies with imaging accounting for 63% of total costs and an average cost of USD 13454 per recurrence detected compared with USD 3924 for cancer antigen-125 testing. Although the cited study focused on ovarian and peritoneal cancers, it highlighted a comparable economic challenge in rectal cancer follow-up, particularly for MACs that require intensive imaging to detect pelvic or peritoneal relapse. Collectively, these data emphasize that both the treatment and surveillance of MAC entail substantial healthcare costs, predominantly driven by surgical complexity, multidisciplinary postoperative care, and the necessity for repeated high-resolution imaging. Strategic resource allocation, favoring centralized surgical expertise, complication prevention, and evidence-based imaging protocols, may optimize cost-effectiveness without compromising oncologic vigilance.

MULTIDISCIPLINARY CONSIDERATIONS

The management of MAC necessitates an integrated, multidisciplinary approach from the point of diagnosis. Histologic subtype must be explicitly addressed during tumor board meetings as it bears prognostic, therapeutic, and technical significance that impacts treatment sequencing. Radiologists, pathologists, oncologists, and surgeons are required to collaborate on a unified strategy for staging, treatment planning, and follow-up, acknowledging that mucinous histology alters both radiologic interpretation and therapeutic expectations. Radiologically, the interpretation of restaging MRI following neoadjuvant therapy presents particular challenges in MAC as residual mucin may mimic viable tumor, thereby potentially causing over-staging or inappropriate exclusion from organ-preserving procedures protocols[53,54]. Thus, radiologists experienced in mucinous morphology are indispensable for accurate response assessment. Pathologists, in turn, play a critical role in distinguishing AM pools from viable carcinoma; the absence of tumor cells within mucin lakes defines a pCR (ypT0N0), a distinction essential for prognosis and further management[42-44]

From an oncologic perspective, TNT remains a prudent strategy for MAC, as it enhances systemic exposure and facilitates optimal surgical conditions. Nevertheless, it is imperative that both patients and healthcare professionals acknowledge its limitations: Although TNT improves treatment compliance and has the potential to control micrometastatic disease, it may not entirely surmount the inherent chemoradioresistance characteristic of MAC[10,12]. Surgeons should thus prepare patients for the high likelihood of requiring definitive resection rather than organ preservation, emphasizing that surgery remains the only curative modality in most cases.

FUTURE DIRECTIONS

Despite growing recognition of its distinctive behavior, MAC remains underrepresented and underestimated in contemporary clinical trials for rectal cancer treatment. The majority of TNT and chemoradiotherapy protocols either exclude or fail to stratify patients based on histologic subtype[24-28]. Consequently, the influence of TNT on MAC remains predominantly extrapolated rather than grounded in direct evidence. Future research should incorporate mucinous histology as a predefined stratification factor to determine whether TNT provides an equivalent, lesser, or different degree of benefit compared to NMAC.

At the molecular level recent research suggests that a subset of MACs characterized by MSI-high or high tumor mutational burden may respond favorably to immunotherapy[7]. The integration of immune checkpoint inhibitors into TNT regimens for these patients signifies a promising advancement in treatment options. Similarly, the development of adaptive TNT protocols in which treatment intensity or modality is modified based on early radiologic or molecular response may facilitate the personalization of therapy for this chemoresistant cohort.

The role of precision imaging also warrants exploration. Advanced MRI radiomics and molecular imaging have shown the potential to distinguish residual tumor from AM, offering a noninvasive means to guide treatment adaptation and surveillance[33]. Furthermore, collaborative international registries focusing specifically on rectal MAC could provide the statistical power needed to refine prognostic models and develop evidence-based, histology-specific management algorithms.

CONCLUSION

MAC of the rectum is a distinct clinicopathologic entity that challenges conventional paradigms of rectal cancer management. It is characterized by larger, poorly demarcated tumors, a predilection for peritoneal dissemination, and a markedly reduced response to neoadjuvant chemoradiotherapy. Meta-analyses consistently demonstrate lower pCR rates (odds ratio approximately 0.38) and higher rates of positive CRMs in MAC compared with NMAC[18,23,38]. Although contemporary TNT trials have transformed rectal cancer management, the advantage of this methodology remains to be validated in MAC, highlighting the ongoing necessity for histology-specific strategies. MAC demands careful preoperative planning, realistic patient counseling, and readiness for technically complex resections, often requiring extended or multivisceral procedures. Accurate radiologic staging, intraoperative judgment, and clear margin achievement remain the cornerstones of curative intent. Postoperatively, vigilant follow-up is warranted, emphasizing cross-sectional imaging to detect peritoneal recurrence and ensuring timely systemic therapy where indicated[47-50,55].

Despite its adverse biological profile, MAC of the rectum does not inevitably confer poorer long-term outcomes. In well-selected patients achieving tumor downstaging after neoadjuvant chemoradiotherapy or TNT and undergoing meticulous R0 surgery, survival may approximate that of NMAC. The key determinant of prognosis thus depends not only on histology but also on the adequacy of staging, treatment response, and surgical accuracy. Nevertheless, rectal MAC management entails greater procedural complexity and potentially greater resource utilization. Extended resections, multivisceral procedures, and the necessity for advanced imaging and adjuvant strategies substantially elevate operative duration, hospitalization period, and associated costs, with a consequent impact on the health-economic evaluation of the treatment planning. Recent analyses have demonstrated that the mean cost of surgery for locally advanced or recurrent rectal cancer rises by 30%-50% when multivisceral or reoperative procedures are required, and postoperative complications contribute disproportionately to total expenditure. These considerations are particularly relevant in publicly funded systems in which maximizing cost-effectiveness without compromising oncologic safety is of utmost importance.

Future research should aim to delineate cost-efficient pathways for MAC management through prospective data collection, biomarker-driven patient selection, and the integration of molecular and imaging predictors into individualized therapeutic algorithms. Multicentric collaboration and translational studies remain essential to bridge the gap between biological understanding and clinical sustainability, ensuring that high-quality, resource-conscious care is achievable for this challenging rectal cancer subtype.