Journal Pre-proof

Mucin-containing rectal cancer: a review of unique imaging,

pathology, and therapeutic response features

David D. Childs M.D. , Caio Max Sao Pedro Rocha Lima M.D. ,
Yi Zhou M.D.

PII: S0037-198X(20)30051-1
DOI: https://doi.org/10.1053/j.ro.2020.07.010
Reference: YSROE 50731

To appear in: Seminars in Roentgenology

Please cite this article as: David D. Childs M.D. , Caio Max Sao Pedro Rocha Lima M.D. ,
Yi Zhou M.D. , Mucin-containing rectal cancer: a review of unique imaging, pathology, and therapeutic
response features, Seminars in Roentgenology (2020), doi: https://doi.org/10.1053/j.ro.2020.07.010

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 Mucin-containing rectal cancer: a review of unique imaging,
pathology, and therapeutic response features

David D. Childs, M.D.1*

Caio Max Sao Pedro Rocha Lima, M.D.2

Yi Zhou, M.D.3

*Corresponding author

1. Associate Professor, Department of Radiology (dchilds@wakehealth.edu)

2. Professor, Department of Medicine, Section of Hematology and Oncology

(pcrochali@wakehealth.edu)

3. Assistant Professor, Department of Pathology (yizho@wakehealth.edu)

Wake Forest University School of Medicine

Medical Center Blvd

Winston-Salem, NC 27157

1
Abstract

Mucin-containing rectal cancer generally includes the histopathologic subtypes of mucinous

adenocarcinoma and signet ring cell carcinoma. Although together they represent only approximately

11-17% of all colorectal cancer cases, they each present unique challenges to the radiologist,

pathologist, and treating clinician. To assist the interpreting radiologist, this article reviews the common

imaging features and pitfalls of MRI-based staging and tumor response evaluation as well as the

radiologist’s role in suggesting the diagnosis – a role traditionally taken by the pathologist but important

nonetheless given the prognostic implications of these tumors. The pathologic, prognostic, and clinical

features of these unique tumors are also reviewed in order for the radiologist to better understand the

multidisciplinary treatment of these tumors.

Keywords: Mucinous, rectal, cancer, imaging, review

Introduction

Colorectal cancer (CRC) is among the most common malignancies worldwide, and a leading

cause of cancer-related deaths (1). In the United States, an estimated 53,200 people will die from CRC in

2020, including 3,640 men and women younger than age 50 (1). Of particular concern is an increasing

incidence among young adults despite an overall decrease in incidence since 1985 (2,3). Multiple studies

have also shown that earlier-onset CRC tends to disproportionately arise from the left colon and rectum

(3). In light of these alarming statistics, there has been an increased effort to examine the diversity of

molecular profiles, clinicopathologic features, and histologic types of rectal cancer with the goal of

selecting patients for optimal treatment algorithms (4). This goal is based on an emerging understanding

that colorectal cancer is actually a complex disease with significant heterogeneity in treatment response

and patient outcomes (5). A number of histologically defined subtypes of colorectal adenocarcinoma are

2
recognized by the World Health Organization (WHO). Subtype classification is therefore one step in the

process of better defining individual patient risk factors and appropriate treatment selection. The

purpose of this article is to discuss the 2 subtypes of rectal carcinoma which are found to contain mucin

at histopathologic examination: mucinous colorectal adenocarcinoma (MAC, which makes up

approximately 10-15% of colorectal carcinomas) and signet ring cell carcinoma (SRCC, which makes up

between <1 and 2.4% (6,7). See figure 1.

Figure 1: Relative frequency of mucin-containing subtypes of rectal cancer.

How do we classify mucin-containing rectal carcinomas?

The exact definition of “mucinous” colorectal cancer is not as simple as one would think. At first

glance, the WHO definition (8) seems straightforward: > 50% of the lesion is composed of pools of

extracellular mucin that contain overt malignant epithelium as clumps, layers, or individual tumor cells

3
including signet ring cells. Carcinoma with mucinous areas of <50% are categorized as having a mucinous

component. An alternate version of a “mucinous” colorectal lesion, however, is signet ring cell

carcinoma (SRCC), if > 50% of the tumor cells have prominent intracytoplasmic mucin typically with

displacement and moulding of the nucleus. Carcinoma with signet-ring cells in <50% of the tumor are

categorized as having a signet-ring cell component. Both variants could be considered to be

“mucinous.” To make matters worse, the WHO classification of mucinous adenocarcinoma allows

histologic heterogeneity, including the presence of signet ring cells within extracellular mucin pools. In

such cases, tumors could potentially satisfy the histopathologic diagnostic criteria for both WHO-defined

“mucinous” colorectal cancer and signet ring cell carcinoma. The situation becomes even more

problematic when one considers that the 2 entities have overlapping image features due to the

presence of mucin in both subtypes (see figure 2). Fortunately, more recent efforts to distinguish these

2 “mucinous” lesions use more stringent histopathologic criteria, partially reflected in the newest (5th

edition) WHO definitions (7-9).

4
Figure 2: A comparison of the pathology and prognostic features of mucinous adenocarcinoma and
signet ring cell carcinoma of the rectum. While each entity has distinct features, there is a component of
overlap.

Why is precise classification important?

The short answer is that a mucinous tumor morphology has been implicated as a possible

independent variable for patient prognosis. The true significance of a mucinous histology has

traditionally been unclear. Some authors have reported that MAC patients have a poorer survival rate

than non-mucinous adenocarcinoma patients, while others have reported similar survival rates (9-17).

5
There has been less uncertainty regarding the implications of SRCC, an uncommon carcinoma that most

frequently arises from the stomach but even more rarely can arise from the rectum (7). This rare

subtype is clearly associated with a worse prognosis and responsible for up to 18% of colorectal

carcinomas in children and adolescents (7). The more inconsistent results for MAC may in part reflect

the often blurred histopathologic distinction between mucinous adenocarcinoma, mucinous

adenocarcinoma with signet ring cells, and signet ring cell carcinoma (9,18).

The significance of the mucinous subtype therefore appears to depend on a more precise

histopathologic definition. Pozos-Ochoa et al. used stricter criteria to distinguish SRCC from MAC with

signet ring cells, and found that patients with SRCC presented at a higher clinical stage, had more lymph

node metastases, and had a worse disease-specific survival compared to those with MAC (7). Others

have also shown that the presence of signet ring cells, even as a minor tumor component, is associated

with worse overall and recurrence-free survival (9,19). The diagnosis of MAC, without signet ring cell

component, itself appears to be associated with a younger age of onset, location in the proximal colon,

more advanced stage at presentation, and poor grade of differentiation (18). A slight predominance in

females has also been shown (14).

Another unique feature of MAC is a possible association with chronic inflammation of the colon

and rectum. Galata et al found that mucinous differentiation was more common than non-mucinous

adenocarcinoma in colorectal cancers occurring in patients with Crohn’s disease (20). An additional

association of MAC with chronic anorectal and rectovaginal fistulas, though believed to be rare, has also

been reported (21). As fistulas are common and malignant degeneration is rare, such tumors are

commonly underdiagnosed (22). Advanced imaging and endoscopy should therefore be considered in

any fistula with an atypical course or recurrence.

6
 A meta-analysis consisting of 44 studies comprising over 220,000 patients indicated a poorer

prognosis for patients with mucinous colorectal adenocarcinoma histology when the stage at

presentation was adjusted (14). That being said, it is still not definite that the overall and cancer-specific

survival between MAC and non-mucinous adenocarcinoma are significantly different when these

associations are controlled in multivariate analysis. Unique clinical features of MAC are summarized in

Table 1.

Table 1: A comparison of clinical, prognostic, and therapeutic response features of conventional and

mucinous adenocarcinoma of the rectum.

7
Implications of tumor histology, molecular changes and systemic therapy

Emerging research has shown that mucinous adenocarcinoma of the colon and rectum does

have distinct genomic aberrations when compared with non-mucinous adenocarcinoma. A recent

somatic mutation analysis of colorectal mucinous adenocarcinoma showed that mucinous tumors are

hypermutated when compared with non-mucinous tumors, with both an increased rate of single-

nucleotide variations and insertion-deletions due to an increased frequency of microsatellite instability-

high (MSI-H) tumors (23). While non-mucinous tumors demonstrated an increased frequency of

mutations in the TP53 gene (associated with the chromosomal instability pathway), mucinous tumors

were more likely to have mutations in v-Raf murine sarcoma viral oncogene homolog B (BRAF) and the

mismatch repair (MMR) protein, MSH6 (associated with the MSI pathway). Such unique molecular

changes are likely to influence tumor response.

The effect of mucinous histology, irrespective of the presence of signet ring cells, on treatment

response has been poorly studied. No prospective trials targeting this distinct population of colon cancer

patients with either cytotoxic chemotherapy or with novel targeting agents, to our knowledge, have

been reported. Retrospective studies suggest that in metastatic colon cancer, MAC histology predicts

poor outcomes. Some investigators believe that mucinous tumors respond differently to chemotherapy

because the mucin may act as a barrier to drug delivery (24). At a molecular level, a poor response has

also been attributed to a relative hypoxic state owing to a reduction in blood supply, which could

diminish the effectiveness of neoadjuvant therapy (25). Lower responses and survival were reported to

FOLFOX (26), FOLFIRI or FOLFOX (27) as first-line therapy with inferior median overall survivals by almost

10 months. In another retrospective analysis, the benefit to FOLFOX in stage III disease was lower for

MAC histology with 3-year disease-free survival of 56.9% compared to 79.2% in the non-mucinous group

[P = 0.04] (28).

8
 Moreover, the addition of molecular target agents like bevacizumab or cetuximab to standard

chemotherapy in metastatic disease appears not to reverse the worse outcomes in the MAC histology

group compared to the non-mucinous population, with median overall survivals of 13.1 and 21.5

months, respectively (13). Sidedness is prognostic and predictive in metastatic colon cancer. Right

colonic primaries, which are commonly found in colonic MAC, bevacizumab added to chemotherapy is

superior to cetuximab and chemotherapy with median overall survivals of 24.5 and 16.4 months,

respectively (29). However, it is unclear if MAC, independent of sidedness, is predictive of superiority of

antiangiogenic agents over EGFR inhibitors in metastatic colorectal cancers.

Despite inferior outcomes in metastatic colon MAC following chemotherapy and biologic agents,

the treatment is still not individualized. Similarly, in earlier stage disease outcomes appears inferior for

MAC patients. While there is no universally accepted explanation for the biological behavior of MAC,

theories have been offered. For example, some have postulated that extracellular mucin may facilitate

the dissection of tumor through the colonic wall (30). As the mucin pool is extruded from the rectal

wall, it could increase the tendency to spread more rapidly than non-mucinous tumors, potentially

explaining how such tumors actually infiltrate beyond otherwise intact fascial boundaries (31).

MAC in the rectum also appears to behave more aggressively than MAC in other colonic

locations, and is prone to have lower survival rates and poorer downstaging (32). Currently, MAC is a

significant predictive factor for poor pathologic complete response to standard neoadjuvant

capecitabine-based chemoradiotherapy in patients with locally advanced CA. MAC rectal cancer

patients receiving preoperative radiation and 5-FU plus leucovorin chemotherapy have a lower tumor

regression (33).

A 2016 meta-analysis that included 8 comparative studies in 1724 patients found that

mucinous rectal cancer was predictive of a poor response to neoadjuvant chemoradiotherapy with

9
lower rates of pathologic complete response and T-downstaging, as well as decreased overall survival

and a higher rate of positive circumferential resection margins (CRMs) (34). This analysis concluded that

while a mucinous histology does not appear to confer a worse overall survival for colonic cancers

(adjusted for stage at presentation), it does confer a poorer prognosis for mucinous rectal lesions.

It has been known for some time that rectal cancers without mucinous features at baseline can

develop mucinous features (so called mucinous differentiation) as a result of neoadjuvant

chemoradiotherapy (32). Acellular mucin pools in the rectal wall and lymph nodes are commonly seen

“mucinous” treatment effects (35). This must be distinguished from tumor displaying mucinous feature

before therapy. While post-therapeutic mucinous differentiation has been well documented for some

time, the significance of the finding is becoming somewhat better understood. Nagtegaal et al. found a

better prognosis for patients with tumors that became mucinous following short-course radiotherapy as

compared to patients with tumors that were mucinous prior to treatment (36). Although

chemoradiotherapy does appear to increase the degree of mucinous differentiation, such tumors do

show regression and down-staging (3). In other words, induced mucinous change does not appear to be

a poor prognostic factor and may be considered a feature of response to pre-operative treatment.

Summary of the latest understanding of mucin-containing subtypes of rectal cancer

Given the latest developments in the understanding of MAC and SRCC, as well as their

distinction, what can we glean from the perspective of implications for the patient?

 Mucinous adenocarcinoma appears to behave more aggressively in the rectum than in other

colonic locations.

 The diagnosis of MAC (without signet ring cells) is associated with a younger age of onset, a

more advanced stage at presentation, and a poor grade of differentiation.

10
  MRC predicts a poor response to traditional neoadjuvant chemoradiotherapy with lower rates

of pathologic complete response and T-downstaging, decreased overall survival and a higher

rate of positive circumferential resection margins.

 Although the histopathologic distinction between MAC and SRCC has traditionally been unclear,

recent evidence suggests that the presence of any signet ring tumor cells (even as a minor

tumor component) is associated with worse overall and recurrence-free survival.

o Using a stricter histopathologic definition, those with SRCC present at a higher clinical

stage, have more lymph node metastases, and have a worse disease-specific survival

compared to those with MAC.

 Given this information, the accurate diagnosis of mucinous rectal lesions therefore becomes

important in prognosis and treatment selection.

Pre-treatment imaging appearance and initial staging

Mucinous adenocarcinoma

MRI

Regarding T- and N-staging, MAC is evaluated with MRI in the same manner as non-mucinous

rectal cancer, based on the TNM staging system and the criteria of the American Joint Committee on

Cancer (AJCC). As for conventional adenocarcinoma, MRI is becoming the preferred modality for

simultaneous evaluation of local and nodal staging (37). The appearance of the tumor is, however,

unique given the markedly high T2 signal as a consequence of copious extracellular mucin. In fact, the

water-like signal on conventional T2 fast spin echo (FSE) sequences can blend imperceptibly with the

surrounding hyperintense adipose tissue of the mesorectum, masking the boundary of the tumor. As

11
mentioned previously, MAC tends to present at a higher stage than non-mucinous adenocarcinoma. This

is usually seen as a diffusely infiltrating morphology, extending beyond a rectal wall that otherwise

appears preserved. As illustrated in figure 3, a diffusely infiltrated wall and lack of contrast with the

adjacent mesorectal fat can lead to under-staging of these tumors.

Figure 3: Initial staging MRI in a 53-year-old male with locally advanced mucinous adenocarcinoma of
the rectum. Sagittal (a) and axial oblique (b) T2-FSE images demonstrate diffuse high-signal infiltration of
the rectal wall, with obliteration of the normal stratigraphic mural anatomy. Note the similar signal
intensity of the tumor and surrounding mesorectal adipose tissue, obscuring the outer tumor margins.

Although not always part of routine rectal cancer protocols, fat suppressed T2-FSE images can

improve tumor margin visualization. Some authors have described the use of 2 different high echo times

with high resolution T2-FSE as a method to improve contrast between tumor and fat (31). At our

institution, we have also found that T1-FSE and low to mid b-value images from diffusion weighted

imaging (DWI) can improve visualization (figure 4). Horvat et al have also described a dark rim

surrounding the T2 hyperintense signal of some mucinous tumors (figure 5) (38). Although variably used

in the United States, dynamic contrast enhanced imaging typically reveals modest peripheral lace-like

enhancement (39). Regarding diffusion-weighted imaging, Wen et al noted higher ADC values for

mucinous as compared to non-mucinous rectal cancers, not surprising given the T2 signal features and

12
lower cellular density (40). They also found significantly higher mean diffusivity and lower mean

kurtosis values in their analysis of diffusion kurtosis imaging.

Figure 4: Staging MRI in a 57-year-old male with mucinous adenocarcinoma. On the axial oblique T2-FSE
image (a), the left anterior tumor margin (ellipse) cannot be discerned. T1-FSE axial oblique image (b)
reveals nodular thickening of the mesorectal fascia (arrows). The involved mesorectal fascia (arrows) is
most prominent on DWI (c, b=400 s/mm2). Fusion image (d) overlays the DWI signal on the conventional
T2-FSE, highlighting the poor visibility of mesorectal fascial involvement (arrow) on standard T2-FSE.
Mucinous adenocarcinoma with malignant epithelial cells in clumps and layers in pools of extracellular
mucin (e and f). Some (arrows) but not all malignant cells (<50%) show signet-ring cell morphology (f).

13
 Figure 5: Staging MRI in a 47-year-old male with mucinous adenocarcinoma with a signet ring
cell component. Sagittal (a) and axial (b) T2-FSE images reveal a mass (arrows) similar in signal to
surrounding mesorectal adipose tissue. While a portion of the mass is circumscribed by T2
hypointensity (small arrows, b), much of the border is not visible (large arrows, b). With fat suppression,
the tumor margins are seen to better effect (arrows, c). Mucinous adenocarcinoma with signet ring cell
features (d and e). Signet-ring cell areas constitute more than 50% of the tumor volume in this small
biopsy material.

Not surprisingly, marked T2 signal is also often visible within metastatic lymph nodes,

mesorectal tumor deposits, and sites of extramural vascular invasion (38). Similar to the primary tumor,

these sites of disease can potentially blend with the mesorectal fatty tissues on T2-FSE and lead to

under-staging (figure 6). The presence of mucin signal within affected regional and distant nodes in the

untreated patient can actually be quite helpful (figure 6), as it is a specific sign of disease as opposed to

the false-positives and false-negatives inherent to the use of size criteria alone (41). As a summary of

14
the above discussion, table 2 compares the typical MR image features of conventional rectal

adenocarcinoma and MAC.

Figure 6: Initial staging MRI in a 50-year-old male presenting with T4N2M1 mucinous adenocarcinoma of
the rectum. Due to the intrinsic T2 signal of mucin, mesorectal tumor deposits (arrows) and metastatic
right iliac node (ellipse) are not well seen on axial oblique T2-FSE image (a). The tumor deposits and
node are now seen as hyperintense structures with the suppression of surrounding mesorectal adipose
tissue on axial fat-suppressed T2-FSE (b) and DWI (c, b=600 s/mm2) images. Osseous metastatic lesion
(thick arrows) is also more apparent on axial fat-suppressed T2-FSE (b) and DWI (c, b=600 s/mm2)
images. Biopsy from the mucinous adenocarcinoma of the rectum (d). The tumor consists of pools of
mucin and tumor with a glandular and cribriform growth pattern (e).

15
Table 2: A comparison of the MRI features of conventional and mucinous rectal adenocarcinoma

CT

The same copious mucin causing elevated T2 signal in MRC results in markedly low attenuation

on CT, as a consequence of the near-water attenuation of mucin. Similar to that seen at MRI,

enhancement tends to be heterogeneous and less than that of non-mucinous lesions (42,43). Small

intratumoral calcifications can also be seen both before and after neoadjuvant chemoradiotherapy

(figure 7) (42,43).

16
Figure 7: Initial staging CT of a 28-year-old female presenting with a large rectal mass classified as
mucinous adenocarcinoma, but with signet ring cell component. Axial (a) and coronal reformatted (b)
images demonstrate a predominantly low attenuation composition, with punctate calcifications (arrows)
which are commonly seen in this subtype. Biopsy from a peritoneal nodule shows poorly differentiated
adenocarcinoma (c). There are mucinous and signet-ring cell features (arrow, d) with focal calcification
(e).

PET

As MRC tends to have a reduced cellular density (tumor cells replaced by mucin in the

microenvironment) compared to other solid neoplasms, some investigators have hypothesized a

relatively lower peak SUV of FDG (30,44). Dos Anjos et al, however, demonstrated that mucinous and

non-mucinous rectal tumors had similar metabolic parameters at baseline PET/CT, with similar SUV

estimates (45). Our institutional experience has confirmed the relatively high peak SUV of FDG in both

the primary tumor and metastases (figures 8,9). There is also some evidence that the use of dual-time-

17
point PET may increase sensitivity for mucinous lesions, due to higher contrast of FDG uptake between

malignant and benign tissue over time (46).

Figure 8: Initial staging exams in a 57-year-old male with locally advanced mucinous adenocarcinoma of
the rectum. The mucin-rich lower rectal mass displays increased signal on the axial oblique T2-FSE image
(a). The mass is quite metabolic on PET-CT (b), with relatively high SUV.

18
Figure 9: MRI and PET-CT in a 63-year-old male who presented with T3N2 low rectal mucinous
adenocarcinoma with signet ring cells also present. The tumor is hyperintense on initial axial T2-FSE
image (arrow, a), with mucin-rich lower para-aortic nodes on fat-suppressed axial T2-FSE image (arrows,
b). Corresponding increase in SUV on axial PET-CT images (arrows, d and e). After neoadjuvant
chemoradiotherapy, the patient underwent abdominoperineal resection. Unfortunately, subsequent
surveillance CT (ellipse, c) demonstrated tumor recurrence in the left psoas muscle which was also
metabolic at PET-CT (ellipse, f).

Signet ring cell carcinoma

CT and MRI

The imaging features of SRCC derive from its typical submucosal pattern of spread, which results

in luminal narrowing but normal appearing mucosa. On cross-sectional imaging, this manifests as

annular thickening and a rigid appearance, sometimes described in the literature as “primary linitis

plastica of the rectum” (47,48). On CT, this may be seen as concentric mural thickening and the so-called

“malignant target sign” (49). Originally described in signet ring cell gastric carcinoma metastatic to the

colon, it consists of thick enhancing outer and inner wall layers separated by a thin hypoenhancing

intervening layer. On MRI, this unique tumor morphology results in a concentric ring pattern (correlate

of the target sign on CT), with the thin middle layer demonstrating relative T2 hyperintensity (50) as

compared to the relatively hypointense inner and outer layers. This morphology differs from that of

MAC, in which the concentric anatomic delineation is obliterated by T2 hyperintense tumor. This

appearance is also different from the classic (benign) target sign in that the middle hypoenhancing layer

is thin in the malignant variety and thick in the benign variety. The sign is also distinguished from benign

entities in that it is short in length, whereas benign disease usually affects longer segments of bowel.

Although the concentric ring pattern visible on T2-weighted imaging has been commonly reported in

SRCC of the rectum, at least one case series has shown that it is not always present (47). Compared to

conventional adenocarcinoma, SRCC tumors have more heterogeneous enhancement and a higher

frequency of peritoneal involvement (43).

19
Prognostic value of staging MRI

In addition to literature demonstrating a worse prognosis for MRC, there is also data showing

prognostic value in pre-therapeutic (staging) MRI image features. Yu and Chand found the presence of

mucin on MRI to be an independent variable for poor disease free survival (51). Barbaro et al found a

significantly higher proportion of patients with metachronous metastases in tumors with mucinous

image features as compared to non-mucinous rectal carcinomas (52). In a similar vein, Oberholzer et al

found that patients with mucinous MR signal features staged as T3 or T4 on pre-therapeutic imaging had

less T-downstaging and a higher rate of positive circumferential resection margin (CRM) as compared to

patients without mucinous image findings (53).

Image-based quantification of the amount of mucin in rectal tumors has also been investigated

as it relates to patient treatment response and outcome. Yu and Chand found that patients who had

tumors with >50% mucinous composition were less likely to have ypT down-staging and had worse 3-

year survival than those patients with no or lesser amounts of mucin (51). Kim et al also noted lower

rates of T-downstaging and higher rates of positive CRM in patients whose tumors had over 30% mucin

composition (54). Using a slightly lower threshold of 20% mucin composition, Miyakita et al found not

only lower rates of T-downstaging and tumor shrinkage, but also that such patients had a greater tumor

volume at presentation (55).

Metastatic patterns and imaging appearances

As noted previously, patients with MRC have been shown to have higher rates of

metachrounous metastatic disease, as well an increased number of metastatic sites, as compared to

those with non-mucinous adenocarcinoma (52). MAC and SRCC both have a higher frequency of lymph

20
node and peritoneal metastases (12,55), possibly as a result of mucin dissection through the tissue

planes with direct extension into the peritoneal cavity. Unfortunately, even with aggressive

cytoreductive surgery and hyperthermic intraperitoneal chemotherapy there is high rate of recurrence

in the signet ring cell subtype (56). Metastatic lesions tend to display similar image features as the

primary tumor (57). In the liver, the significantly increased T2 signal could cause confusion with

hemangioma (58,59). In such a circumstance, dynamic post-contrast imaging provides a vital

distinguishing clue (figure 10). Whereas hemangiomas display a progressive nodular discontinuous

enhancement pattern, mucinous hepatic metastases typically display modest heterogeneous

enhancement (60).

Figure 10: 28-year-old female with T4N2M1 mucinous adenocarcinoma of the rectum. Fat suppressed
axial T2-FSE image(a) from staging MRI reveals mucin-rich left iliac node (arrow). Synchronous
metastatic liver lesions are markedly hyperintense on axial fat-suppressed T2-FSE image (b). While the
T2 appearance overlaps that of benign hemangioma, the solid peripheral rim enhancement visible on
post-contrast T1-weighted GRE images (c) distinguishes these metastatic lesions from benign entities.
The lesions are also metabolic on PET-CT (d).

21
Importance of imaging diagnosis

Mucinous adenocarcinoma

While MRI usually does not significantly contribute to the actual diagnosis of rectal cancer, it can

be quite useful in recognition of the MAC subtype. One would assume that endoscopic biopsy offers the

highest accuracy for this task. Unfortunately, pre-treatment biopsy has been shown to reveal less than

20% of cases subsequently shown to be mucinous tumors (61). Using the image finding of more than

50% high signal intensity mucinous stroma as a diagnostic criterion in a cohort of patients with rectal

cancer, Yu et al found that MRI was superior to preoperative biopsy, revealing a mucinous histology in

18% of patients in the cohort, compared to 5% noted on initial biopsy (51). All of the lesions designated

as mucinous on MRI were subsequently confirmed on histopathology. It is therefore imperative that the

interpreting radiologist describe mucinous features at the time of initial staging MRI.

Signet ring cell carcinoma

The histopathologic diagnosis of SRCC can also be problematic with routine endoscopic biopsy

due to the infiltrative behavior of this neoplasm, which can actually spare the mucosa. At colonoscopy,

therefore, the lumen may be narrowed but without a visible mucosal lesion. Unless biopsies include the

deeper involved tissues, false negative results can occur (48). Unfortunately, this scirrhous morphology

can also mimic inflammatory or ischemic conditions, with segmental thickening/stricture and a target

appearance (62) but without the shouldering typical of conventional adenocarcinoma. Such findings in a

younger patient can be particularly problematic, as malignancy is not expected even though SRCC is a

common cause of rectal carcinoma in adolescents and young adults (7). In this light, the radiologist has

an important role in recognition of a potential scirrhous morphology on cross-sectional imaging and

suggesting deep wall biopsies.

22
MRI and tumor response

Utility of MRI after neoadjuvant therapy

Current National Comprehensive Cancer Network (NCCN) guidelines advocate neoadjuvant

chemoradiotherapy for patients with T3-T4N0 disease, any T and N1-2 disease, and locally unresectable

or medically inoperable tumors (63). Pre-treatment image-based staging is therefore intrinsic to initial

treatment decisions. What, however, is the role of “restaging” MRI after completion of

chemoradiotherapy? One role would be for selection of patients who may be suitable for the so-called

“watch-and-wait” approach. Distinct from the traditional approach of total mesorectal excision

following chemoradiotherapy, this tactic is meant to identify those patients with a complete clinical

response in order to spare them the morbidity of surgical resection (64). In addition to endoscopy,

tumor markers, and physical exam findings, imaging plays a major role in the recognition of a complete

response (37). Another role for MRI following neoadjuvant therapy is the assessment of T-downstaging

and tumor regression. Even though the re-evaluation of T stage can affect surgical treatment decisions,

however, the significance of a quantitative assessment of tumor regression lies in patient prognosis (65-

67). While a histopathologic evaluation of relative proportions of residual tumor and degree of

morphologic changes such as fibrosis and mucin production is currently the reference standard for

tumor regression grading, correlative studies have also examined the utility of MRI-based systems. Such

systems commonly include T2 signal features and ADC values derived from DWI; some investigators

have also utilized perfusion imaging using pharmacokinetic modeling and time-resolved imaging (37,68).

While the staging accuracy and histopathologic agreement of these systems are less accurate than that

seen for pre-treatment MRI, there does appear to be relevance for the prediction of survival (68-71).

23
 Imaging and the treatment response of mucinous adenocarcinoma

Unfortunately, MAC presents unique challenges in the arena of post-therapeutic imaging. Such

challenges are again seen to arise from the histopathologic features of the tumor itself. As noted

earlier, the abundant extracellular mucin pools significantly increase the T2 signal of these tumors.

Investigators have shown that the imaging extent of this mucin remains largely unchanged after

chemoradiotherapy (55,72), and that the proportion of mucin on post-treatment MRI is only useful if it

is increased (denoting a positive response) (54). This creates an issue in that reductions in tumor T2

signal and volume are major image features used to assess positive treatment response for rectal

adenocarcinoma (37). Given that these tumors are composed of >50% mucin pools, even those cases

with a positive response would likely display similar T2 signal and tumor volume, even if no tumor cells

are present in the mucin pools (73). Post-contrast imaging can also prove problematic. Since MAC

typically displays only modest peripheral lacelike enhancement, even a significant decrease in the

degree enhancement following chemoradiotherapy may appear quite subtle on visual inspection (39).

The same factors also create difficulty in evaluation of potential N- and T-downstaging following

chemoradiotherapy. Locally advanced MAC typically displays T2 hyperintense mucin pools (with viable

tumor cells) which extend beyond the rectal wall. Even if the tumor cells beyond the rectal wall

disappear following neoadjuvant therapy, the acellular mucin will appear identical and thus result in

over-staging or even upstaging (73,74). From a histopathology perspective, acellular mucin should not

be used to assign T or N stage. Tumor margin or lymph nodes with mucin are considered positive only if

the mucin pools contain malignant cells (figure 11) (35).

24
Figure 11: 63-year-old-male with locally advanced mucinous adenocarcinoma of the rectum. Axial fat-
suppressed T2-FSE image (a) from staging MRI reveals mucin-rich metastatic nodes (arrows) in the
retroperitoneum. After neoadjuvant chemoradiotherapy, surveillance CT (b) reveals no change in node
size, and similar mucin content resulting in low attenuation. Abdominoperineal resection and nodal
dissection one week later revealed only acellular mucin in the nodes, without viable tumor cells (c). This
case highlights the difficulty in evaluating tumor response in mucin-rich nodes.

Given such difficulties in tumor response assessment, how should the radiologist approach

these difficult cases? Park et al addressed this very dilemma with the development of a MRI-based

model specific for mucinous adenocarcinoma of the rectum (72). In their patient cohort, they found that

responding patients did have a reduction in volume, although it was modest and the tumor generally

remained bulky after chemoradiotherapy. The changes in volume were related to shrinkage of the soft

tissue components which were a minority of overall tumor volume. Not surprisingly, they found that

MRI overestimated both T and N stage due to the presence of acellular mucin. What is the lesson for the

radiologist interpreting a “restaging” MRI? It is best to ignore the mucinous portions of MRC, instead

concentrating on changes occurring in the solid soft tissue components (figure 12). When evaluating the

MRI-based tumor regression grade (TRG), Park et al used T2-weighted signal intensity to distinguish

between mucin (high signal intensity), tumor (intermediate signal intensity), and fibrosis (low signal

intensity). Utilizing this approach in a modified MRI-based response system (see Table 3), this group was

able to distinguish responding from non-responding patients when comparison was made to the

pathologic tumor regression grade.

25
Figure 12: MRIs before and after neoadjuvant chemoradiotherapy in a 28-year-old female with rectal
mucinous adenocarcinoma and signet ring cell features. Although much of the tumor volume is
composed of T2 hyperintense extracellular mucin (sagittal and axial T2-FSE images, a and b,
respectively), there are lower signal areas of solid soft tissue (arrows) with denser tumor cellularity.
Correspondingly low ADC values (arrows) are also seen on axial ADC map derived from multi b-value
DWI (c). Sagittal and axial T2-FSE images following therapy show no significant change in the
hyperintense extracellular mucin, but a significant reduction in the more hypointense solid tissue
(arrows, d and e). The ADC map (f) also reveals a decrease in soft tissue component size and an increase
in ADC pixel values.

26
Table 3: Modified MRI-based tumor regression grade scoring system utilized by Park et al (72) for
mucinous adenocarcinoma of the rectum. Unique features of this schema include distinction of soft
tissue and mucin using T2 signal, as well as a lack of fibrosis assessment for grades 3-5.

Future directions

While the conventional CT and MR imaging features of MAC and SRCC are certainly useful in the

radiologic recognition of mucin-containing rectal carcinomas, emerging advanced imaging techniques

are currently being evaluated in the hope of providing additional clinically useful information. As an

extension of DWI, Wen et al. applied diffusion kurtosis imaging for the purpose of rectal cancer subtype

and histologic grade distinction (40). They did find higher mean diffusivity and ADC values for MAC

rather than conventional adenocarcinoma, but were not able to distinguish histological grades. CT

texture analysis, a noninvasive biomarker used to assess the heterogeneity in routine diagnostic images,

has shown some promise in the diagnosis mucin-containing tumor subtypes. Yue et al, for example,

found three 3-dimenstional CT-derived texture parameters that were useful in differentiating SRCC from

27
conventional colorectal adenocarcinoma (75). In a separate study, Campagnola et al evaluated CT-

derived texture parameters in 204 patients with colorectal adenocarcinoma (76). When comparing MAC

with conventional tumor, they noted a significant difference in mean tumor densities (lower for MAC)

and multiple texture parameters, reinforcing the subjective observation that MAC tends to have more

heterogeneous enhancement. Another computer-aided method recently applied to these tumors is

radiomics, in which extracted image parameters describe the spatial distribution and heterogeneity of

voxel intensities in conventional medical images. Ge et al, for example, found that a combination of

radiomic features performed better than conventional CT features in differentiating mucinous from

conventional rectal adenocarcinoma (77). In another study, Liu et al noted that some image parameters

were promising in distinguishing normal from metastatic lymph nodes in patients with colorectal MAC

(78). While none of these techniques are directly applicable to patient care at this time, it is hoped that

the further development of quantitative techniques will improve the diagnostic yield of CT and MRI in

the rectal cancer population.

Conclusions

A substantial minority of untreated rectal cancers can be categorized as “mucinous.” Mucinous

adenocarcinoma is a subtype comprising 10-15% of rectal cancer cases and has unique histopathologic,

molecular, imaging, and therapeutic response features, all of which present challenges to both the

radiologist and treating physician. Given the low diagnostic sensitivity of endoscopic biopsy, the imaging

recognition of this subtype is crucial, as MAC predicts a poor response to traditional neoadjuvant

chemoradiotherapy, decreased overall survival and a higher rate of positive circumferential resection

margins. The initial staging and subsequent tumor response assessment are made difficult by the

infiltrative, mucin-rich tumor morphology. The radiologist must understand the common resultant

pitfalls to minimize initial staging errors. Additionally, a tailored interpretive approach is required in the

28
post-treatment setting, recognizing inherent limitations and focusing on the relatively small solid soft

tissue component of the tumor. MAC can also have histopathologic features which overlap those of

signet ring cell carcinoma, a much rarer subtype of rectal cancer. Newer pathology classification

schemes appear to offer improved distinction between these entities, although the presence of signet

ring cells in any amount is associated with worse overall and recurrence-free survival. As with MAC,

recognition of distinct imaging features (particularly the concentric ring appearance) by the radiologist is

important to suggest this rare diagnosis. With continued refinement in the image interpretation of these

challenging tumors, it is hoped that more precise therapeutic selection can lead to improved patient

outcomes. Additionally, prospective clinical trials in colon and rectal cancer patients stratifying for MAC

are desperately needed.

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