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Review ArticleHistopathological regression of gastric adenocarcinomaafter neoadjuvant therapy: a critical reviewEDUARDO HENRIQUE CUNHA NEVES FILHO, ROSANE OLIVEIRA DE SANTANA,LUIZ VIANNEY SALDANHA CIDRAO NUNES, ADRIANA PINHEIRO BEZERRA PIRES andMARIA DO PERPC19ETUO SOCORRO SALDANHA DA CUNHAInstituto do Cancer do CearC19a, Fortaleza/CE, BrazilNeves Filho EHC, SantAna RO, Nunes LVSC, Pires APB, Cunha MPSS. Histopathological regression ofgastric adenocarcinoma after neoadjuvant therapy: a critical review. APMIS 2017; 125: 7984.As the perioperative chemotherapy has been widely implemented on the management of gastric cancer patients, hetero-geneity of clinical outcomes has been evidenced in parallel to dierent histopathological regression pattern of gastriccancer cells. Tumor histological response to preoperative therapy has been graded by various systems in order to cate-gorize the amount of regressive changes induced by chemotherapy in relation to residual tumor. In this context, tumorregression grading (TRG) systems might provide important prognostic information as the variety of tumor responsemay imply on dierent clinical outcomes with impact in survival rates. Moreover, gastric cancer behavior varies enor-mously upon individual factors such as histological classification and tumor anatomic site of involvement that havebeen shown to aect the TRG interpretation. On the other hand, some studies have assessed the role of molecularmarkers as a predictor of tumor response to neoadjuvant chemotherapy in terms of TRG. Thus, the aim of this reviewis to evaluate how TRG has been interpreted in gastric cancer, discuss their clinical and prognostic relevance and alsoaddress the molecular markers involved in this process.Key words: Gastric cancer; tumor regression grading; neoadjuvant chemotherapy.Eduardo Henrique Cunha Neves Filho, Patologia, Instituto do Cancer do CearC19a, Rua Papi Junior, 1222 CEP 60.430-230Fortaleza/CE, Brazil. e-mail: .brGastric cancer (GC) is the fifth most commonmalignancy in the world, with a high lethality asthe third leading cause of cancer death in bothsexes worldwide (1). The latter rate is partly due tothe advanced stages at diagnosis (2). In this con-text, many attempts have been made to improvepatients survival, tailoring the extent of surgeryand adding the administration of neoadjuvant and/or adjuvant therapy (24). From the 2000s the stan-dard treatment in patients with locally advancedgastric cancer is no longer based on surgery alonesince perioperative radiochemotherapy orchemotherapy regimens has been shown to havemore favorable eects on curative resection rates,disease-free survival and overall survival (58).Histological regression in many tumors afterchemotherapy is believed to be an important mor-phological parameter for evaluating tumor responseto perioperative treatment, once the eects ofneoadjuvant therapy may be established and objec-tively graded by histopathological investigation(6, 9, 10). In gastrointestinal malignancies, severaltumor regression grading systems (TRG) have beenproposed to categorize the amount of regressivechanges after cytotoxic treatment, mostly quantify-ing the amount of therapy induced fibrosis relatedto the residual tumor cells or estimating thepercentage of residual tumor in comparison to theprevious tumor site (10).Regarding to gastric adenocarcinomas, TRG hasbeen shown to provide highly valuable prognosticinformation, as they have correlated significantly withsurvival, tumor size and lymphatic vessel invasion insome studies (912). In addition, TRG seems to beassociated with dierent biological characteristics instomach cancer, such as primary tumor localizationand histological classification (12). Nevertheless, thereis still a lack of research in this field.Received 8 August 2016. Accepted 2 November 201679APMIS 125: 7984 2017 APMIS. Published by John Wiley & Sons Ltd.DOI 10.1111/apm.12642Thus, the aim of this review is to present howTRG has been interpreted in gastric cancer, the dif-ferent patterns of response among the histologicalsubtypes of gastric adenocarcinoma in terms ofpathological regression, discuss their clinical andprognostic relevance and also address the molecularmarkers involved in this process.CLASSIFICATION OF TUMOR REGRESSIONIN GASTRIC CANCERTRG as a measurement of response to neoadjuvanttreatment in gastrointestinal malignancies wasfirstly proposed by Mandard et al. in 1994 for usein the assessment of pathological specimens ofsquamous cell carcinoma of the esophagus follow-ing perioperative radiochemotherapy. In this sys-tem, five histological grades were proposed basedon viable tumor tissue at the ratio of fibrosis (13).Similarly, in 2005 Rodel et al. in multi-center studycarried out in Germany used a complex five scorefor the estimation of tumor regression in rectal ade-nocarcinoma (14). Both studies were able to corre-late their proposed TRG to survival.A TRG specific for gastric adenocarcinoma wassuggested by the study of Ninomiya et al. in 1999,in which 18 locally advanced gastric cancer(LAGC) specimens from patients submitted toneoadjuvant chemotherapy (NACT) were dividedinto grades 03, based on the amount of fibrosisand/or necrosis over the remaining viable tumorcells (Table 1) (15). Although this study associatedthe TRG to the carcinoma histological subtypes, ithas not evaluated this parameter in terms of sur-vival rates. Becker et al. in 2003 in a German studyrecruited 36 patients with LAGC undergone toperioperative etoposide, doxorrubicin, and cisplatin(9). Dierently, this study proposed a grading oftumor regression based on the percentage of micro-scopic residual tumor tissue in relationship with themacroscopically identifiable tumor bed and strati-fied in three grades (Table 1) (Fig. 1), which weresignificantly associated to survival. In addition,TRG was also associated to classic gastric cancerprognostic parameters such as tumor size and angi-olymphatic invasion. This system was successfullyvalidated by the same group in 2011 as theyincreased patient sample to 480 cases of gastric car-cinoma, rendering TRG as independent prognosticfactor for this malignancy (11).Comparisons between studies and use ofresponse criteria in routine practice are hamperedby the lack of a standard grading system for gas-tric cancer. Few studies have compared the dier-ent scoring systems in terms of theirreproducibility and ability to indicate prognosis.Mirza et al. compared Mandards, Ninomiyasand Beckers TRG systems in order to assesstheir reproducibility and survival prediction forgastric and esophagogastric junction carcinomas(16). According to their findings, both Mandardand Becker TRGs were associated with prognosis,being the Becker system the most reproducible.Similar studies have been also carried out in eso-phageal/gastric-esophageal junction and rectaltumors (17, 18).PROGNOSTIC IMPLICATIONS OF TRGMany studies have been assessing the importanceof the use of TRG in gastric cancer pathologicalevaluation (11, 12, 15). The general observation isthat patients who had complete pathological regres-sion have a better outcome.Table 1. Comparison of the criteria assessed in examples for TRG systems used in gastric cancer evaluationBecker et al. (9) Ninomiya et al. (15) Mandard et al. (13)Ia. No residual tumor cells overmacroscopic tumor bed withregression changes0. No evidence of regression changes 1. Complete regressionIb. 50% of residual tumor cells overmacroscopic tumor bed with or withoutregression changes2. Moderate change necrosis or disappearance ofthe tumor is present in more than 2/3 of thewhole lesion, but viable tumor cells remain4. Predominance oftumor tissue overfibrosis3. Marked change the whole lesion falls intonecrosis and/or is replaced by fibrosis, with orwithout granulomatous changes. No viable tumorcells are observed5. No evidence of fibrosisand/or regressionchanges80 2017 APMIS. Published by John Wiley & Sons LtdNEVES FILHO et al.A multivariate analysis in Beckers study foundthat TRG were significantly associated to overallsurvival (11). On the other hand, another study car-ried out in Germany by Schmidt et al. found thatmultivariate analysis did not confirm TRG as anindependent prognostic factor for gastric cancer. Ithighlighted, however, that TRG remains an impor-tant piece of information after perioperativechemotherapy as it represents an in vivo assesmentof chemosensitivity of the tumor and might be usedas a stratification criterion for tailored postopera-tive treatment (19). Moreover, it is noteworthy thatboth studies suggest a clear discrimination betweenresponders (Becker TRG Ia + Ib) and non-respon-ders (Becker TRG 2 and 3) patients.It is well-established that the biological behaviorof gastric adenocarcinoma varies upon its primaryanatomic localization and histological subtypingaccording to Laurens classification (9, 12). In termsof pathological response to neoadjuvant treatment,Reim et al. (12) found that more distal cancers ofLaurens diuse subtype have the lowest probabilityof significant tumor regression after perioperativechemotherapy. Likewise, Becker et al. (11) demon-strated a negative impact of diuse type of canceron tumor regression. Although this study did notfind a significant dierence between tumor localiza-tion and TRG, proximal stomach carcinomas weremore likely to achieve major tumor regression.Additionally, a study also pointed that well-dier-entiated tubular tumors were more related to abetter histological response than signet-ring cellstumors in the Japanese population (15). This datasuggest that these features might predict responseto NACT so may be useful for therapeutic patientselection.An important limitation to the understanding ofTRG prognostic relevance is the high prevalence ofthe current studies developed in Japan and Europe,where gastric cancer epidemiology and presentationmay significantly dier in comparison to countriessuch as Brazil and Chile where gastric tumors isalso considered a public health issue (1). In fact, alarge multi-centric study involving gastric cancer isstill required in order to validate these data and toestablish a practical and reproducible TRG withhigh prognostic value.COMPARISON BETWEEN TRG AND OTHERPOST-TREATMENT EVALUATION METHODSThe measure of NACT eects has been evaluatedin many ways with dierent prognostic meanings.Classically, the assessment of downstaging eectsaccording to the TNM classification has beenwidely used as the main criteria for evaluation ofneoadjuvant response. However, this method reliesover a documentation of a decrease in pathologicvs preoperative clinical T/N categories. As preoper-ative staging techniques, such as endoscopic ultra-sound, computed tomography scans and magneticIA IBII IIIFig. 1. Examples of tumor regression grades according to Becker. 2017 APMIS. Published by John Wiley & Sons Ltd 81GASTRIC CANCER PATHOLOGICAL REGRESSIONresonance imaging scans, are limited in their abilityto provide accurate information on these categories,the evaluation of response comparing clinical-radi-ological stage with pathological stage might overes-timates the rate of tumor downstaging caused byneoadjuvant therapy (14). Moreover, in our dailypractice, we often observe that a dramatichistopathological response in gastric cancer is notaccompanied by a significant improvement of theTNM staging, as the T criteria is categorized by thedepth of tumor invasion and even small clusters ofremaining tumor cells may overrate the final patho-logic staging. In this context, Suarez et al., studyingcolorectal cancer, compared the TNM staging andthe TRG according to Mandard in terms of sur-vival indicator and found that regression grade wasshown to be a better prognostic factor (20).Another diusely used method of neoadjuvanttherapy assessment is the Response Evaluation Cri-teria in Solid Tumors (RECIST), considered thegold standard in the evaluation of tumor response.Nevertheless, its application in gastric malignanciesis limited, as it requires the presence of a measur-able lesion, which seldom occurs in resectable gas-tric cancer. Furthermore, as the RECIST guidelinecautioned, the primary lesion of the digestive tractis not suitable for the measurable lesions in termsof reproducibility (21). When compared to theTRG, a Japanese study in 2014 highlighted that thehistological criteria showed higher response assess-ment validity than RECIST and yield the best sur-rogate endpoint for overall survival (22).However, although the assessment of TRG ingastric cancer seems to be a promising indicator oftumor response to neoadjuvant therapy, it have notentered clinical practice as only few studies havebeen published in this context. Further investiga-tions are necessary in order to validate this data.PRACTICAL IMPLICATIONS OF USING TRGFOR GASTRIC CANCER IN THEPATHOLOGIST ROUTINEAs the tumor histological response has been grad-ing dierently, there is also no consent regarding tothe general work-up of post-treatment gastric can-cer specimens. For instance, when Becker et al. (9)in 2003 proposed their TRG a grossing protocol inwhich they cross-sectioned serially at 0.5 cm inter-vals the whole tumor and identifiable surroundingscarring tissue (tumor bed) was applied. On theother hand, Mandard et al. (13) performed a semis-erial sectioning of the entire specimen. In our rou-tine, the grossing protocol used in post-treatmentgastrointestinal specimens includes serial sections at1.0 cm intervals of the tumor and, separately, ran-dom samples of the transition between viablemacroscopic tumor and adjacent scarring tissue,which seems to be representative and very cost-eective.The histological evaluation of TRG involvesmostly the viable tumor/fibrosis ratio, which mightbe challenging to the pathologist on regular hema-toxylin and eosin stain. Desmoplastic reaction in ahypocellular tumor area may be interpreted aspost-treatment fibrosis and it can overestimate his-tological tumor response. Additionally, in post-treatment gastric cancer samples, scattered cellswith clear cytoplasm and peripheral nuclei amongscar tissue may also be dicult to dierentiatebetween reactive histiocytes and reminiscent signet-ring cells, which distinction would be fundamentalto report the TRG. Thus, special stains such elasticvon Gieson stain to distinguish between desmo-plasia and scarring and periodic acid-Schi (PAS)to distinguish signet-ring cells and histiocytes mightbe very helpful (9, 11). Immunohistochemical stud-ies using an epithelial marker such as CytokeratinAE1/AE3 may also be applied in order to dieren-tiate reminiscent scattered tumor cells and inflam-matory or reactive stroma cells (9).MOLECULAR MARKERS OF TRG INGASTRIC CANCERThe factors that may lead to a dierent individualtumor response to neoadjuvant treatment are stillnot well-understood on the molecular point of view.In fact, few studies have assessed the molecularaspects of tumor regression grading in gastric can-cer.Apparently, alterations of the DNA repair sys-tem may be useful as a biomarker of tumorresponse to platinum-based chemotherapy in gas-tro-esophageal cancer. Platinum interacts withDNA to form predominantly intra-strand crosslinkDNA adducts that trigger a series of intracellularevents that lead to cell death (23). The nucleotideexcision repair (NER) pathway is involved on theprocessing and repairing of these DNA damages.In this context, inactivation of NER results in plat-inum hypersentitivity (24). Of the several factorinvolved, ERCC1 has been shown to have animportant role in NER (24). Several studies havesuggested ERCC1 expression as a chemossensitivitymarker for gastric cancer, with inconsistent results(2527). Conversely, Farred et al. in 2010 con-ducted an investigation of potential biomarkers thatmay have the ability to predict TRG response ingastro-esophageal cancer after platinum-based82 2017 APMIS. Published by John Wiley & Sons LtdNEVES FILHO et al.therapy, focusing in key DNA repair enzymes.They showed that nuclear expression of ERCC1 issignificantly associated to high TRGs, implying thatERCC1 expression may be a promising predictivemarker of chemoresistance (28).Additionally, few studies have been associatedTRG in gastric cancer to micro RNA (miRNA)profiles (29, 30). miRNA are a class of endogenous,small non-coding RNAs that regulated gene expres-sion by inhibiting mRNA translation and havebeen indicated as key in the carcinogenesis of solidtumors, including gastric cancer. So that, Liu et al.investigated 68 patients with locally advanced gas-tric cancer undergoing neoadjuvant therapy fol-lowed by surgical resection and found that lowlevels of let-7i miRNA were significantly correlatedwith a poor histopathological response (29). Fur-thermore, a study carried out in Germany by per-forming microarray analyses identified a dierentialmiRNA expression profile depending on thehistopathological response of patients with alsolocally advanced gastric cancer undergoing multi-modality treatment (30).A recent meta-analysis evaluated whether geneticpolymorphisms were associated to tumor responseto pre-operative chemotherapy in terms ofhistopathological regression. Their findings suggestthat patients carrying the wild (CC) genotype ofthe MTHFR C677T polymorphism, a commonalteration involving the methylenetetrahydrofo-latereductase (MTHFR) in which the polymorphiccarrier presents a lower enzymatic activity and ispointed to predict response to fluoropyrimidine-based chemotherapy, might benefit from neoadju-vant treatment compared with CT or TT carriers,as the CC genotype was significantly correlatedwith a better histopathological response. Otherspolymorphisms, such as MTHFR A1298C andEGFR G497A, on the other hand, showed no cor-relation with TRGs (31).CONCLUSIONSIn summary, TGR has been shown as a promisingsurvival marker in gastric cancer, although largerstudies involving dierent pop

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