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10.1245/s10434-006-9163-0
Annals of Surgical Oncology 14:853-861 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Neoplastic Mesorectal Microfoci (MMF) following Neoadjuvant Chemoradiotherapy: Clinical and Prognostic Implications

Carlo Ratto, MD1, Riccardo Ricci, MD2, Vincenzo Valentini, MD3, Federica Castri, MD2, Angelo Parello, MD1, Maria A. Gambacorta, MD3, Numa Cellini, MD3, Fabio M. Vecchio, MD2 and Giovanni B. Doglietto, MD1

1 Department of Clinica Chirurgica, Catholic University, Largo A. Gemelli, 8, 00168, Rome, Italy
2 Department of Pathology, Catholic University, Largo A. Gemelli, 8, 00168, Rome, Italy
3 Department of Radiotherapy, Catholic University, Largo A. Gemelli, 8, 00168, Rome, Italy

Correspondence: Address correspondence and reprint requests to: Carlo Ratto, MD; E-mail: carloratto{at}tiscali.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated on for rectal cancer following neoadjuvant chemoradiation.

Methods: A case series of 68 patients with extraperitoneal rectal cancer treated with neo-adjuvant chemoradiation and surgery (including total mesorectal excision) were investigated for presence of neoplastic MMF.

Results: MMF were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of the bowel wall (P = 0.0006), Mandard’s tumor regression grading (P = 0.0006), and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. One out of nine pT0 or TRG1 patients (11.1%) had distant metastases compared with 15 out of 59 pT1–4 or TRG2–5 (25.4%, P = 0.70).

Conclusions: A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induced complete regression of primary tumor (pT0–TRG1), we found that node metastases and neoplastic MMF also disappeared. These features should be confirmed to assess the impact of these microfoci in treatment decision making in rectal cancers.

Key Words: Rectal cancer • Surgery • Chemoradiation • Local recurrence • Mesorectum


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Neoplastic involvement of the mesorectum is frequently observed in patients with rectal cancer and correlated to lack of local control.1–14 Recent advances in the treatment of rectal cancer suggest total mesorectal excision (TME) to achieve better local control1,3,8,13,15–20 and improve long-term results.1,3,13,17,18 A number of clinical studies have confirmed that adjuvant21–34 or neoadjuvant35,36 therapy increases the curative rate compared with surgery alone. Indeed, preoperative use of radiation or chemoradiation therapy seems to offer the best chances in terms both of local tumor control and anal sphincter sparing.37–50 In fact, the effects of combined chemoradiotherapy on the primary tumor are well known, including, in many cases, reduction in volume both of the exophytic and transmural components of the tumor mass and "sterilization" of the metastatic lymph nodes in the mesorectum. These features, when achieved, result in tumor downstaging,37,40–42,45,46,48–62 which could then be excised with better resection margins. It is still debated whether to reduce resection margins when a very good response is obtained so that a tumor candidate for abdominoperineal excision could undergo a sphincter saving procedure before neoadjuvant therapy.37,62,63 Encouraged by the excellent response to chemoradiotherapy (complete absence of tumor bulk), some authors have suggested that local excision of the tumor site be performed.64,65

Primary tumor staging and lymph node status are the most important factors to be considered in the TNM staging system and in planning the therapeutic approach. However, neoplastic microfoci, discontinuous to the primary tumor, have frequently been found in the mesorectum, both in early and advanced tumors.1,4,6,7,13,66–69 Furthermore, the negative prognostic impact of these foci has been demonstrated in our previous study and in other series.67,69

In the present study, the incidence and clinical significance of neoplastic MMF have been analyzed retrospectively in patients operated upon for rectal cancer following neoadjuvant chemoradiation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A total of 68 patients (39 males, 29 females; mean age: 60.6) with extraperitoneal rectal cancer treated between 1995 and 2002 entered the study. Primary tumor was studied with endoscopy plus biopsy (for histological assessment), transrectal ultrasound (US), pelvic computed tomography (CT), and/or pelvic magnetic resonance imaging (MRI). Thereafter, a clinical staging of the tumor was derived (cT and cN).

Treatment
All patients were submitted to a multimodal treatment protocol including preoperative chemoradiation, surgery, intraoperative radiation therapy (IORT), and, in selected cases, postoperative chemotherapy. In particular, 24 patients were treated with concomitant chemoradiation for a total dose ranging from 45 to 48 Gy with conventional fractionation. Chemotherapy consisted of administration of bolus IV mitomycin C (MMC) 10 mg/m2 on day 1 plus 24-h continuous infusion of IV 5-fluorouracil (5FU) 1,000 mg/m2, which was delivered in the first and last weeks of radiotherapy. Six to 8 weeks after the end of external beam treatment, during surgery, and after tumor removal, a 10-Gy boost dose was delivered to the presacral region with 6 MeV electrons. The other 44 patients received external-beam radiotherapy for a dose of 45 Gy plus 5.4-Gy boost to reach a total dose of 50.4 Gy. Chemotherapy consisted of raltitrexed (3 mg/m2) on days 1, 19, and 38 of radiation delivery. Six to 8 weeks after the end of external beam treatment, during surgery, and after tumor removal, a 10-Gy boost dose was delivered to the presacral region with 6 MeV electrons in these patients also.

Radical tumor resection included TME, as described by Heald et al.,1,2 and locoregional lymphadenectomy extended to the origin of inferior mesenteric artery from the aorta. A minimal distal margin of 2 cm from the edge of the tumor was achieved when resecting the specimen in all cases.

In 17 patients with a stage cT4 N0-2 tumor, postoperative chemotherapy was carried out [5FU bolus, 350 mg/m2 for 5 days, plus folinic acid bolus (L-isomer), 100 mg/m2 in six to nine cycles with a 28-day interval].

Pathologic Examination
Methods used in specimen examination have been described elsewhere.67 Briefly, after bowel removal, the specimen (including the mesorectum) was opened along the antimesenteric border and pinned to a cork board. The mesentery was dissected 2 cm from the bowel wall, and intermediate and principal lymph nodes were accurately identified (macroscopically and upon palpation) and examined as follows: After fixation in 10% formolsaline solution, serial transverse sections were cut at 5-mm intervals through the tumor, bowel wall, and mesorectum in continuity, as described by Quirke et al.70 All slices were embedded and stained with hematoxylin and eosin (H&E). One pathologist (RR) examined all the slices in order to establish direct tumor infiltration and lymph node involvement in the mesorectum. Direct tumor infiltration was classified as follows: no tumor, within the bowel wall, beyond the bowel wall invading the perirectal fat, or infiltrating organs or structures adjacent to the mesorectum. Absence or presence of lymph node involvement was registered (classified as pN– or pN+, respectively). Particular attention was paid to identifying neoplastic MMF; these were defined as mesorectal deposits of adenocarcinoma, discontinuous from the primary tumor, with no evidence of nodal tissue. Neoplastic lesions were classified as endovascular (cancer deposits in blood vessels, VASC+), endolymphatic (MMF in lymphatic nonnodal vessels, LYMPH+), perineural (cancer cell aggregates between the fasciculus and perineurium, NEUR+), or isolated (tumor MMF, without evidence of lymph node tissue, in the mesorectal fatty tissue, at a distance from the main tumor, ISOL+). Moreover, patients were classified as p-mesorectum–or p-mesorectum+ according to the absence or presence of any type of tumor involvement of the mesorectal tissue (direct infiltration of the primary tumor mass, lymphnodal spread, neoplastic MMF). Taking into consideration the effects of chemoradiotherapy on the primary tumor bulk, each specimen was also classified according to Mandard’s tumor regression grade (TRG) criteria71 (Table 1Go).


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  		TABLE 1. Modified Mandard’s tumor regression grade (TRG) criteriaa
 
Follow-Up Schedule
After the end of the treatment protocol, patients were monitored at follow-up with physical examination, complete blood cell count, serum chemistry tests, and liver US every 3 months for the first 2 years and every 6 months thereafter. Chest X-ray and abdominal–pelvic CT were performed every 6 months during the first 2 years and every 12 months thereafter. Development of any local recurrence and/or distant metastases was recorded during follow-up. Median follow-up was 39 (range 6–168) months. None of the patients were lost to follow-up.

Statistical Evaluation
Relationships between clinical and pathological parameters were analyzed in all patients, attention being focused on the presence or absence of MMF. To establish the clinical and prognostic meanings of these deposits, patients were allocated to two subgroups: those with MMF were classified as MMF+ and those without as MMF–. Moreover, MMF+ patients were stratified according to the different modes of microscopic spread (VASC+, LYMPH+, NEUR+, ISOL+), and comparison was made using Pearson’s chi-square test (P < 0.05 being considered statistically significant). Overall, disease-free, local-recurrence-free, and distant-metastasis-free survival rates were calculated using the Kaplan–Mayer method; differences between groups were evaluated with the log-rank test, with P < 0.05 being the limit of significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The efficacy of preoperative chemoradiation therapy was demonstrated in the present series by downstaging both T and N. T downstaging was achieved in 43 patients (63.2%); 26/51 cases (49.0%) classified as cT3, and all 17 cT4 were downstaged after neoadjuvant therapy. None of patients had residual tumor. As to lymph node involvement, chemoradiation therapy led to downstaging in 73.8% of patients (48/65) classified as cN+. After preoperative treatment, 24 cN1 and 16 cN2 cases became pN0 and eight cN2 patients became pN1. Interestingly, in nine patients (13.2%), the primary tumor mass disappeared, and lymph nodes were negative. Following Mandard’s TRG criteria,71 nine patients (13.2%) were classified as TRG1, 12 (17.6%) as TRG2, 30 (44.1%) as TRG3, 12 (17.6%) as TRG4, and five (7.4%) as TRG5. Table 2Go shows correlation data between TRG classification and lymph node involvement.


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  		TABLE 2. Correlation data between lymph node involvement and Mandard’s tumor regression grade (TRG) classificationa
 
Pathologic examination revealed mesorectal involvement in 46 patients (67.4%), direct tumor infiltration of the mesorectum was observed in 38 patients (55.9%), involvement of the mesorectal lymph nodes was found in 26 patients (38.2%), and the presence of microscopic neoplastic MMF was observed in 26 cases (38.2%). Table 3Go shows the patterns of mesorectal involvement. Neoplastic MMF were present in 26/46 (56.5%) patients with mesorectal involvement; these MMF were part of the first and second more frequent patterns of mesorectal involvement.


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  		TABLE 3. Patterns of mesorectal involvement
 
With regard to the types of neoplastic MMF, 16 patients (23.5%) were classified as VASC+, 12 (17.6%) as LYMPH+, 13 (19.1%) as NEUR+, and eight (11.8%) as ISOL+. In three cases (4.4%), the presence of MMF was the only mode of mesorectal involvement. One pattern of MMF was present in 12 patients (46.2%), two patterns were present in six (23.1%), three patterns were present in seven (26.9%), and all four patterns were present in one (3.8%). Details of neoplastic MMF patterns are shown in Table 4Go. Correlation data regarding the presence/absence of MMF and tumor staging parameters are listed in Table 5Go.


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  		TABLE 4. Patterns of neoplastic mesorectal microfoci (MMF)
 

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  		TABLE 5. Incidence of neoplastic mesorectal microfoci (MMF) related to the other clinical and pathological parameters
 
A higher incidence of MMF was found in tumors classified as cT4 before neoadjuvant therapy (8/17 patients; 47.1%) than in tumors classified as cT3 (18/51 patients; 35.3%) (P = 0.39). Only three patients were classified as cN–; in two of them (66.7%), pathology examination detected MMF. Among cN+ patients (65 cases), neoplastic MMF were found in 24 specimens (36.9%). However, differences in MMF rates between cN– and cN+ patients were not statistically significant (P = 0.58). Pathologic involvement of the mesorectum by direct infiltration of the primary tumor mass was associated with a significantly increased incidence of neoplastic MMF (P = 0.0006): 19/36 (52.8%) tumors infiltrated the mesorectum throughout the entire rectal wall and both cases with infiltration of the perirectal organs. On the other hand, 5/21 (23.8%) patients with a tumor limited to the bowel wall had MMF. None of the nine patients with complete tumor disappearance displayed MMF. With regard to pathologic lymph node involvement, 13/42 (31.0%) of pN0 patients presented MMF, as did 9/19 (47.4%) of pN1 patients and 4/7 (57.1%) of the pN2 patients. Overall, 13/26 (50%) of pN+ patients displayed neoplastic MMF (P = 0.27).

According to Mandard’s TRG criteria,71 neoplastic MMF were not detectable in any of the nine TRG1 patients but were identified in 4/12 (33.3%) TRG2 patients, 10/30 (33.3%) TRG3 patients, 10/12 (83.3%) TRG4 patients, and 2/5 (40.0%) TRG5 patients. Differences were statistically significant (P = 0.0006).

Table 6 shows the correlation data between each pattern of neoplastic MMF and the other pathological features. The incidence of VASC+ was significantly related to depth of tumor infiltration through the bowel wall (P = 0.0006), mesorectal involvement (P = 0.0001), and TRG grading (P < 0.00001). LYMPH+ was significantly correlated with bowel-wall infiltration (P = 0.03), lymph node involvement (P = 0.001), mesorectal infiltration (P = 0.001), and TRG grades (P = 0.002). On the other hand, the NEUR+ rate increased significantly in relation to mesorectal infiltration (P = 0.0007) and TRG scale (P = 0.03). However, no significant relationship was demonstrated between ISOL+ and the pathological parameters evaluated.

In one patient (1.5%), local recurrence developed; the primary tumor in this patient was classified as pT3 N1 M0, TRG 5, and neoplastic MMF were VASC+, LYMPH+, and ISOL+. None of the patients with pT0 or TRG1 presented local recurrence. Only 1/9 pT0 or TRG1 patients (11.1%) had distant metastases compared with 15/59 pT1–4 or TRG2–5 patients (25.4%, P = 0.70).

When overall, disease-free, local-recurrence-free, and distant-metastasis-free survival rates were calculated related to presence of MMF (MMF– vs. MMF+), a trend of worse survival rates was evidenced (35.2% vs. 25.2%, 32.4% vs. 29.5%, 26.2% vs. 17.9%, 32.4% vs. 25.8%, respectively), but differences were not statistically different (P = 0.41, P = 0.27, P = 0.46, P = 0.30, respectively). Similar findings were found when the survival analysis was restricted to only ISOL, LINF, VASC, and NEUR microfoci.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The efficacy of TME in the curative treatment of extraperitoneal rectal cancers is now well defined.1,3,8,13,15–20 Correct routine use as a policy of surgical strategy has shown indisputable results.11,72 Therefore, some authors have standardized strict pathological criteria to make certain that adequate "specimen-oriented surgery"7 has been performed. On the other hand, the progress made in the clinical application of radiation therapy and chemotherapy has thrown further light on what could be the potential oncological benefit of an association of these therapies with surgery. Even if results of definitive studies are still awaited, a number of clinical reports appear to suggest that the preoperative is more effective than the postoperative approach73,74 and that chemoradiotherapy would give better results than radiotherapy alone.21,25,27,28,31–34,37,45,75–77 However, new, intriguing aspects are currently gripping researchers. Groups of surgeons are endeavoring to identify the correct criteria in treating patients with surgery alone (using the TME technique). Cooperative research between surgeons and oncologists is evaluating the best modalities (doses, timing, drugs, etc.) in the chemo-radio-surgical approach in order to achieve regression both of the primary tumor tissue (within and beyond the rectal wall) and the lymph node metastases. All these different "philosophies of cure" have the same common denominator: the "mesorectal tissue is oncologically dangerous" (as underlined by Heald in the invited editorial to our earlier article67). Thus, both supporters of TME and supporters of therapy integration are exerting maximum efforts on the mesorectum.

Previous studies, including one of our own, have enphasized the occurrence of neoplastic MMF not related to the primary tumor mass.1,4,6,7,13,67–69 The incidence of these findings ranges between 31% and 45%,1,4,6,7,13,67–69 featuring different patterns (endovasal, endolymphatic, perineural, and isolated), which can be associated with each other in a variety of situations. In some patients, the presence of neoplastic MMF was the only evidence of mesorectal involvement of the tumor.67 We demonstrated the negative prognostic impact of these MMF,67 an aspect confirmed in other reports.6,13,66,69 Moreover, in a previous study,67 we reported a similar occurrence of MMF in patients submitted to surgery alone (44.7%), and those who underwent an integrated protocol including the association of radiation or chemoradiation therapy and surgery (43.3%). To our knowledge, no data exist in the literature concerning these features. Since that aspect was not a primary aim of that study, our patients were dishomogeneous as far as modalities of neoadjuvant therapy were concerned. Moreover, the incidence of MMF was not related to the response to treatment.

Since, in our opinion, these questions remain very important, we aimed in this study to specifically investigate the incidence of MMF in patients treated with preoperative chemoradiation only. The modalities of pathological investigations were the same as those in the previous study, but the results were related not only to the clinical and pathological staging criteria but also to Mandard’s TRG criteria,71 a valid classification of the effects produced by chemoradiation on a solid tumor. Despite the efficacy of neo-adjuvant treatment and the marked downstaging achieved in the majority of these patients, in about two thirds, the mesorectum was found to be involved—in a large percentage (38.2%) due to the presence of MMF. It is worthwhile noting that in three cases (4.4%), MMF were detected in the mesorectum only. These data would confirm our previous findings that, overall, in a group of patients with rectal cancer, the occurrence of neoplastic MMF does not appear to be influenced by the treatment used. However, correlation analysis between the presence of MMF and pathological parameters showed the most interesting data: The incidence of MMF was found to be directly related to the depth of primary tumor infiltration; more that half the patients had MMF if the tumor invaded the perirectal tissues, with statistically significant differences in comparison with cancers limited to the bowel wall (MMF in 23.8% of cases). Cases with lymph node involvement also showed a higher incidence of MMF when compared with pN0 patients. Possibly, the most interesting findings were those concerning patients (nine cases) who presented complete regression of the primary tumor mass following neoadjuvant therapy and standard treatment for removal of the rectum using the TME technique; all were also node negative. No neoplastic MMF were detected in the mesorectum of these patients, who, thus, were determined "sterilized" from the tumor. Furthermore, when patients were classified according to the TRG criteria, TRG1 cases did not show any MMF while a progressively increasing incidence of MMF was observed in more advanced grades.

Although endovascular MMF were more frequently observed in comparison with other types, no significant differences were detected; isolated MMF were identified in 11.8% of patients. Almost 50% of the MMF+ cases had only one pattern whereas the others showed two, three, or even four patterns of MMF. Results of the correlation analysis between MMF types and the pathological parameters were statistically significant. VASC+ and LYMPH+ cases were significantly related both to the depth of primary tumor mass infiltration and TRG classification. NEUR+ patients showed a significant relationship with TRG grading but not with primary tumor infiltration (even if an increasing incidence of perineural MMF was observed as depths progressively increased). Only ISOL+ were not statistically correlated with the pathological features (probably due to the small number of cases displaying these MMF).

Results of this study could have a number of clinical implications. If further investigated and confirmed, in a larger number of cases, evidence of neoplastic MMF should have an impact on tumor stage and be considered a relevant parameter in the classification systems for rectal cancers. This concept should be supported by the prognostic influence of these MMF. Unfortunately, a trend of worse survival rates was found in MMF+ patients when compared with the MMF– group but without statistical significance; this feature was mostly due to the limited number of patients available in this study, and an analysis including a large accrual of patients should verify our findings.

Moreover, the impact of MMF in treatment decision making could be crucial. Over the last decade, the application of neoadjuvant chemoradiation therapy seems to have led to a marked regression of advanced rectal tumors. In about 10–30% of cT3 or cT4 cancers, this combined treatment has led to a complete pathologic response (pT0, TRG1),38–41,45,47,50,51,53,54,56–61,78–86 and lymph node involvement would also seem to have disappeared, as noted in some reports.51,58,59 These features are associated with a very rare, sporadic development of local recurrence,40,48,51,57–59,65,83,84,87 and, in some reports,21,29,75,78,84–86,88–91 an improvement in long-term survival. Moreover, with the influence of MMF on patients prognosis not yet being clear, the therapeutic role of adjuvant chemotherapy in MMF+ cases needs to be elucidated.

At this point, confirmation is needed—in large, controlled studies—that, in a subset of patients with clinical stages II–III rectal cancers, neoadjuvant chemoradiation therapy may induce complete tumor regression, including the primary tumor mass, lymph node metastases, and MMF, as shown in our pT0–TRG1 cases. Only after such confirmation could this subset of patients be investigated with a view to a minimal therapeutic approach. On the other hand, the frequent persistence of neoplastic MMF, even after a good but partial response to neoadjuvant therapies, suggests the need to resect the tumor using scrupulous TME. It would be of interest to assess the role of MMF+ in addressing patients to postoperative chemontherapy.

Received for publication September 12, 2005. Accepted for publication April 27, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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