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What Is the Prognostic Value of (y)pT and TRG?

  • Fabio M. Vecchio
  • Riccardo Ricci
Chapter

Abstract

The different types of scoring systems for grading the response to preoperative chemoradiotherapy are summarized and compared also by explanatory tables. The authors present several grading scoring systems, ranging from three to five grades. The prognostic significance and the clinical impact of tumor regression grade are reported. TRG determination appears to be the logical complement to traditional pathologic TNM staging, and combining TRG and TNM appears to optimize the management of rectal cancers treated with preoperative chemoradiotherapy. As TRG defines the amount of residual cancer cells after neoadjuvant therapy, further investigations are mandatory in order to define the quality of neoplastic cells and their behavior, especially in patients without lymph node metastasis. Identification of factors, indicating a more aggressive phenotype and/or resistance toward chemoradiotherapy, may contribute to improve the prognostic value of TRG and to allow tailoring of treatment.

Abbreviations

CAP

College of American Pathologists

CRT

Chemoradiotherapy

CSS

Cancer-specific survival

DFS

Disease-free survival

m-RCRG

Modified version of rectal cancer regression grade

RCPath

Royal College of Pathologists

RCRG

Rectal cancer regression grade

TRG

Tumor regression grade

ypTNM

TNM staging after neoadjuvant therapy

63.1 Introduction

As for tumor in general, prognosis of rectal tumors strongly depends on the stage of advancement of cancer; this parameter is efficiently represented by the TNM stage. In case of cancers treated with preoperative chemoradiotherapy (CRT), the tumor stage is assessed using the same parameters as in untreated cases, but in the final TNM codification, a “y” precedes each category letter, meaning the occurrence of preoperative therapy. ypTypN staging, like ordinary TNM staging of tumors not treated prior to surgery, obviously conditions prognosis. However, this staging is a static assessment of tumor advancement which does not convey any information at all concerning tumor response to preoperative CRT, a parameter likely bearing an intrinsic prognostic weight. Thus, the comparison between pre-CRT TNM and post-CRT ypTypN(ypM) stages (i.e., the evaluation of so-called downstaging) appears preferable when the evidentiation of CRT effects is needed. Finally, various pathologic methods for assessing post-CRT tumor regression grade (TRG) have been proposed, constituting a way alternative to TNM staging for prognosticating tumors surgically excised post-CRT. This chapter will compare these prognostication methods when applied to post-CRT rectal cancers, highlighting advantages and disadvantages of each of them both singly considered and in combination, according to the most recent literature.

63.2 Definition and Grades of TRG

Tumor response to preoperative CRT varies from the total regression of the tumor with complete absence of tumor cells to no regression at all. Many studies have demonstrated that a good response to preoperative CRT is a favorable prognostic factor. Therefore, an accurate evaluation of tumor response is useful for predicting oncologic outcomes and planning further treatment. The term tumor regression grade (TRG) was firstly introduced by Mandard et al. in 1994 [11]. The authors examined 93 resected specimens from patients affected by esophageal carcinoma treated with preoperative CRT. They found that TRG was a significant predictor of disease-free survival (DFS). In their study, Mandard et al. defined five grades of TRG, ranging from TRG 1, characterized by complete regression, to TRG 5, with no regression at all. Tumor regression was assessed by examining the rate between residual cancer and regressive changes as represented by stromal fibrosis. On the basis of the combination of these findings, tumor regression was classified as reported in Table 63.1.
Table 63.1

Mandard and Dworak TRG

Mandard TRG

Dworak TRG

Definition

Score

Score

Definition

Absence of tumor cells

1

4

No tumor cells (total regression)

Residual cancer cells scattered through the fibrosis

2

3

Very few (difficult to find) tumor cells in fibrotic tissue

Fibrosis outgrowing residual cancer cells

3

2

Dominant fibrotic changes with few tumor cells or groups (easy to find)

Residual cancer cells outgrowing fibrosis

4

1

Dominant tumor mass with obvious fibrosis

Absence of regressive changes

5

0

No regression

The main advantage of Mandard’s TRG was that regression was assessed by an overall simple and reproducible method, leading to its prompt application also to rectal cancer treated with preoperative CRT. In 1997 Dworak et al. adopted a very similar grading of regression examining the surgical specimens of 17 patients with rectal carcinoma after CRT [5]. Like Mandard et al., they designed five regression grades, but defined and named them in a different way. Dvorak TRG varies from grade 0 with no regression to grade 4 with no tumor cells (see Table 63.1, showing the correspondence between the Mandard and Dworak TRG systems). In the specimens studied by Dworak, no cases of total regression were observed after standardized pathologic work-up, i.e., embedding of the whole suspicious area in paraffin blocks and step sectioning, if necessary. Dworak and colleagues pointed out that the demonstration of residual tumor depended mainly on the accuracy of the pathologic technique.

In 2002, two other different regression grading systems were proposed by Ruo et al. [16] and by Wheeler et al. [26]. Ruo and colleagues analyzed the long-term prognostic significance of selected clinicopathologic factors, including the extent of pathologic response in 69 patients with locally advanced rectal cancer. They recorded rectal cancer response as percentage histologic response, ranging from no evidence of treatment effect (0%) to a complete response with no viable tumor identified (100%) by a six-point grading scale reflecting the amount of tumor tissue with respect to the area of “tumor treatment effect” defined as replacement of neoplastic glands with loosely collagenized fibrous tissue and scattered chronic inflammatory cells, as follows [16]:

No response

Grade response 0

1–33%

Grade response 1

34–66%

Grade response 2

67–95%

Grade response 3

96–99%

Grade response 3+

100%

Grade response 4

Wheeler et al. quantified the histologic regression of rectal cancer after irradiation in a study on 42 patients. They proposed a three-point rectal cancer regression grade (RCRG) [26]. RCRG 1 was characterized by “good” radioresponsiveness with sterilization or only microscopic residual foci of adenocarcinoma. In RCRG 2 macroscopic disease was present in association with marked fibrosis. Finally, RCRG 3 indicated a “poor” response with abundant macroscopic disease and little or no fibrosis. Wheeler stressed the importance of determining RCRG by the consideration that, since radiotherapy reduced the number of viable cells present in the field of treatment, it seemed appropriate to use a pathologic staging system that measured tumor regression in addition to the traditional TNM staging after neoadjuvant therapy (ypTNM).

Rödel et al. in 2005 evaluated the prognostic significance of TRG on surgical specimens of 385 patients treated with preoperative CRT [15]. They defined a five-point TRG derived from Dworak scale with some modifications (see Table 63.2). Rödel incorporated Dworak TRG 3 and 2 in TRG 3 and split Dworak TRG 1 in TRG 2 and 1. TRG 0 and 4 remained unmodified. Moreover, grades were defined in an attemptively more objective manner. On this basis Rödel grouped TRG by a three-grade system.
Table 63.2

Dworak and Rödel TRG

In 2005 Ryan et al. proposed a modified Mandard score with a three-point TRG, in which TRG 1 grouped the Mandard TRG 1 and TRG 2, TRG 2 was equivalent to Mandard grade 3, and TRG 3 grouped the Mandard TRG 4 and TRG 5 (see Table 63.3) [17]. In their study, based on 60 patients with a mean follow-up of 22 months, the authors emphasized that TRG 1 and 2 could be considered a complete pathologic response and that the modified three-point TRG had the advantage of better reproducibility, with similar prognostic significance.
Table 63.3

Mandard TRG and Ryan and Vecchio modifications

 

Mandard score

Ryan score

Vecchio score

Absence of tumor cells

1

1

1

Residual cancer cells scattered through the fibrosis

2

2

Fibrosis outgrowing residual cancer cells

3

2

Residual cancer cells outgrowing fibrosis

4

3

3

Absence of regressive changes

5

Another method of grading the degree of tumor regression post-CRT in rectal cancer was the system proposed in 2007 by Royal College of Pathologists (RCPath) included within the second edition of dataset guidelines for colorectal cancer reporting [27]. The system defined the following categories:
  1. A.

    No residual tumor cells and/or mucus lakes only

     
  2. B.

    Minimal residual tumor, i.e., only occasional microscopic tumor foci are identified with difficulty

     
  3. C.

    No marked regression

     

In 2008, Quah et al. reported the three-tier “Memorial Sloan Kettering Cancer Center” (MSKCC) grading of tumor regression based on the proportion of nontumoral tissue within the lesional area (tumor response 100%, 86–99% and <86%) [14].

In 2009, Bateman et al. proposed a modified version of Wheeler RCRG (m-RCRG), in which the key change was the inclusion of a more detailed definition of each category (Table 63.4) [1]. In their study performed by reviewing the rectal excision specimens from 54 patients, Bateman et al. compared the utility and reproducibility of three different TRG scoring systems: the Mandard TRG, the modified RCRG, and the three-tier method at that time used by the RCPath cancer dataset. They concluded that all three scoring systems were usable in a diagnostic setting and all with acceptable degrees of interobserver agreement. The authors favored the use of m-RCRG for the assessment of rectal cancer specimens after neoadjuvant therapy because providing the optimum balance between applicability and the accurate recording of low, moderate, and high tumor regression. They also suggested that regression grade scoring must be entirely based on the microscopic presence of residual tumor, rather than including macroscopic features suggestive of residual tumor.
Table 63.4

Wheeler RCRG and Bateman m-RCRG

RCRG 1

Sterilization or only microscopic foci of adenocarcinoma remaining, with marked fibrosis

m-RCRG 1

The macroscopic features may be varied. Microscopy reveals no tumor epithelium or scattered foci of malignant epithelium comprising <5% of the overall area of abnormality. Mucin pools may be present but do not contain malignant epithelium

RCRG 2

Marked fibrosis, but macroscopic disease present

m-RCRG 2

The macroscopic features may be varied. Microscopy reveals a combination of viable tumor epithelium and fibrosis. Malignant epithelium comprises 5–50% of the overall area of abnormality

RCRG 3

Little or no fibrosis with abundant macroscopic disease

m-RCRG 3

The macroscopic and microscopic features may not be significantly different to cases in which neoadjuvant therapy has not been given. Over 50% of the area of abnormality comprises malignant epithelium. Some fibrosis may be present but no more than that commonly seen as desmoplastic stroma in cases where no neoadjuvant therapy has been given

Also in 2009, the College of American Pathologists (CAP) guidelines suggested the following four-tier system, derived from Ryan 2005 classification [25]:
  • Grade 0, complete response: no residual tumor

  • Grade 1, moderate response: minimal residual cancer

  • Grade 2, minimal response [without further details]

  • Grade 3, poor response: no definite response identified

In 2010, Vecchio et al. examined the relationship between TRG and 10-year outcomes in 502 patients with locally advanced rectal cancer treated with preoperative RCT [24]. They proposed a simplification of Mandard score in three grades (see Table 63.3):
  • TRG 1: complete regression with absence of tumor cells

  • TRG 2: incomplete regression with fibrosis predominant on cancer cells

  • TRG 3: absent or poor regression with residual cancer outgrowing fibrosis

The endorsement of a three-tier system is supported by the overlap of the recurrence-free survival curves of grades 2 and 3 in both the Mandard and Dworak-Rödel scoring systems [21].

In 2010, the seventh edition of the AJCC Cancer Staging Manual classified the pathologic response to preoperative RCT according to the CAP 2009 guidelines, with the following specifications (Table 63.4):
  • 0 (complete response): no viable cancer cells

  • 1 (moderate response): single cells or small groups of cancer cells

  • 2 (minimal response): residual cancer outgrown by fibrosis

  • 3 (poor response): minimal or no tumor kill; extensive residual cancer [6]

The AJCC tumor regression grading system was also adopted by the RCPath [10].

Despite all tumor regression grading systems appear predictive of tumor recurrence, all of them suffer from areas of possible ambiguity which cause various degrees of interobserver variability. This depends on lack of objective criteria for separating some categories, such as Mandard TRG 3–4 and 4–5 [11]; on ambiguous definitions, such as “tumor cells difficult [or easy] to find” in the Dworak system [5]; on how to define the original tumor area to be adopted as the 100% for calculating the percentage of residual tumor, as happens in the Bateman [1] or in the MSKCC systems [14]; or on possible confusion in detecting tissue-type representatives of tumor regression [2]. With regard to the latter aspect, although most of tumor regression grading systems refer generically to “fibrosis” as the hallmark of regression, fibrous tissue is not the only tissue type that can replace tumor after chemoradiation. In fact, variable amounts of granulation tissue, histiocytic reaction, hemosiderin-laden macrophages, foamy macrophages, cholesterol deposits, foreign body reaction, and dystrophic calcification can also be found. The possible confusion caused by this histologic variability is increased by the lack of specificity, in terms of tumor substitution, of some of these tissue types, since fibrosis and granulation tissue can follow endogenous tumor necrosis in untreated carcinomas [20].

Another troubling issue of tumor regression grading systems is the paucity of published recommendation for handling of surgical resection specimens. Nowadays, there is general agreement that a complete response cannot be ascertained unless the whole suspicious area is embedded and analyzed [20]. In particular, the second European Rectal Cancer Consensus Conference recommended to start taking five blocks from the tumor site and, in case no viable tumor is found, to go on including the whole tumor area and, if still no tumor is detected, to section additional three levels from each block; only if tumor remains still undetected, a complete tumor regression can be asserted [22].

63.3 Prognostic Significance of TRG

Apart from the chosen method, tumor regression after preoperative RCT has been found to have prognostic significance [15, 23].

In the conclusions of their study, Ruo et al. found that a marked response to preoperative radiotherapy ± chemo was clinically associated with fewer recurrences and good long-term outcome, but was not an independent predictor of recurrence-free survival [16].

Rödel et al. reported that 5-year DFS after CRT and curative resection was 86% for TRG 4 with no tumor cells (complete pathologic response), 75% for grouped TRG 2 + 3 with regression ≥25% of tumor mass (intermediate pathologic response), and 63% for grouped TRG 0 + 1, with regression <25% of tumor mass (poor tumor regression) [15]. Rödel et al. concluded that complete and intermediate pathologic response suggested improved DFS after preoperative CRT [15]. They found that complete regression of the primary tumor was associated with better control of disease in lymph nodes (ypN positive, 10%) and a minor risk to develop distant metastases (DFS, 86%). Intermediate tumor regression was associated with intermediate risk of lymph node involvement (ypN positive, 32%) and an intermediate prognosis (DFS, 75%). Patients with tumors showing poor tumor regression also had more advanced ypT categories, higher incidence of nodal involvement (ypN positive, 42%), and unfavorable outcome (DFS, 63%). In their study, Rödel et al. did not find any significant relationship of TRG to specific pretreatment characteristics, such as the cT and cN categories, and hypothesized that tumor regression after preoperative CRT was a multifaceted phenomenon that appeared to be associated with smaller, less aggressive disease and may also correspond to the molecular tumor profiling regulating treatment response. The prognostic value of TRG according to Rödel has been recently confirmed in a prospective study with long follow-up [7].

The three-tier MSKCC grading of tumor regression was found not only to be statistically significantly associated with recurrence-free survival [14] but also to outperform both the Mandard and Dworak/Rödel scores by analyzing association with recurrence and survival using concordance index [21].

Vecchio et al. examined the relationship between TRG and outcome in 144 patients with rectal cancer treated with preoperative CRT and with a median follow-up of 72 months [23]. They quantified TRG in five grades according to Mandard score and combined TRG 1–2 and TRG 3–5. They found that TRG was a predictor for local failure, metastases-free survival, DFS, and overall survival. By multivariate analysis only ypN (p < 0.001) and TRG (p = 0.005) significantly predicted DFS. Moreover, TRG predicted the incidence of positive nodes (p < 0.0001). Vecchio et al. concluded that, given the ability of TRG to predict N+ disease, it might be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure following CRT such as local excision rather than radical surgery.

When compared for prediction of recurrence with three-tier Mandard, Dworak/Rödel, and MSKCC systems, the four-tier AJCC showed a better concordance index, although without reaching a statistical significance [21].

The prognostic value of tumor regression grade following preoperative chemoradiotherapy for locally advanced rectal adenocarcinoma keeps being confirmed in recent studies, either using the Mandard [3, 4, 13] or the Rödel [7] scores. Unlike esophageal carcinoma, where only complete regression has been reported to be an independent prognosticator [8], recent reports (a meta-analysis and a prospective study with long follow-up) confirmed the prognostic value of partial regression in rectal cancer [7, 9].

63.4 Toward the Best Prognostication Method of Post-CRT Rectal Adenocarcinoma

As mentioned at the beginning of this chapter, evaluating tumor response to CRT using TNM staging or the various TRG scores is not equivalent. Results may be misleading depending on the method used. Moreover, interrelationships between descriptors proper of either TNM or TRG grading systems appear to exist.

There is evidence that positive lymph nodes after preoperative CRT, indicating an aggressive potential of the malignant cells associated with resistance toward CRT, suggest an unfavorable prognosis irrespective of any TRG of the primary tumor [15]. In a recent paper, Min et al. investigated the clinical impact of TRG after preoperative CRT for locally advanced rectal cancer especially in lymph node-negative patients [12]. They studied a group of 178 patients who had cT3–cT4 tumors and examined the prognostic significance of TRG in comparison with histopathologic staging. They found that TRG was an independent prognostic factor for the cancer-specific survival (CSS) of the ypN0 patients and that TRG had a stronger impact on the CSS of ypN (-) patients (P = 0.002) than on that of the ypN (+) patients (P = 0.521).

When singly considered, evaluation of tumor regression has been reported to be a better prognostic factor than downstaging [19]. Coherently, although both tumor regression and T stage are commonly found to bear a prognostic value on univariate analysis, the latter (unlike the former) does not usually survive among independent prognosticators on multivariate analysis [3, 4, 7]. The weaker prognostic value of downstaging/TNM stage when compared to tumor regression grade is not surprising considering that an originally T3 tumor may have regressed little but nevertheless have changed from T3 to T2 stage or, conversely, have responded almost completely, having been reduced to a single tumor aggregate located in the perirectal tissue but, because of this, have remained T3: in both these occurrences, TNM stage would be misleading in representing preoperative CRT effect and post-CRT residual tumor burden.

Reasonably, the prediction of CSS is expected to be optimal if both information on the number of residual cancer cells (by TRG) and on their location in rectal wall, perirectal tissue, and locoregional lymph nodes (by ypT ypN stage) are considered. TRG determination would thus be the logical complement to traditional ypTNM staging when considering patients for further adjuvant therapy.

With this perspective, TRG is mentioned in the AJCC Cancer Staging Manual (but not in the UICC TNM Classification of Malignant Tumors) as an additional prognostic factor, although without being integrated into the final staging system [6, 18].

Nodal status appears a stronger prognostic predictor than tumor regression in locally advanced rectal cancer treated with preoperative chemoradiotherapy [3, 4, 7]. Based on this evidence, and on the ability of nodal status to predict prognosis in groups with homogeneous regression grade, scores combining TRG and nodal status have been proposed, constituting a coherent score system combining TRG and TNM parameters. These scores showed a high prognostic value [3, 4]. In particular, a score integrating TRG, circumferential resection margin status, perineural invasion and nodal status showed a prognostic value significantly more powerful than both TRG and AJCC staging in predicting both DFS and overall survival [4].

Conclusions

TRG definitely bears a strong independent prognostic value. Nevertheless, regression grading systems may further improve by refining criteria both in terms of reproducibility of parameters to be evaluated (i.e., defining them more objectively) and of standardization of surgical specimen processing. T stage appears a prognosticator weaker than TRG in locally advanced rectal adenocarcinoma after preoperative radiochemotherapy, unlike N status. Combining TRG with classical TNM parameters into an integrated staging system is a promising method for optimizing the prognosis of rectal cancer treated with preoperative CRT. Finally, as TRG defines the amount of residual cancer cells after preoperative CRT, further investigations are mandatory in order to define the quality of neoplastic cells and their behavior, especially in patients without lymph node metastasis. Identification of factors indicating a more aggressive phenotype and/or resistance toward CRT may contribute to improve the prognostic value of TRG and to allow tailoring of treatment, including surgical options more conservative with respect to those currently adopted.

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© Springer-Verlag Berlin Heidelberg 2018

Authors and Affiliations

  1. 1.Department of PathologyUniversità Cattolica S.CuoreRomeItaly

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