Postneoadj Reporting

252 Am J Clin Pathol 2008;129:252-262252 DOI: 10.1309/CCR3QN4874YJDJJ7

American Society for Clinical Pathology

Anatomic Pathology / ESOPHAGEAL CARCINOMAS AFTER CHEMORADIATION

Histopathologic Examination and Reporting of EsophagealCarcinomas Following Preoperative Neoadjuvant Therapy

Practical Guidelines and Current Issues

Fuju Chang, MD, PhD, Harriet Deere, MBBS, MRCPath, Ula Mahadeva, MBBS, MRCPath, and Simi George, MBBS, MRCPath

Key Words: Esophagus; Residual carcinoma; Neoadjuvant chemoradiotherapy; Tumor regression grading; Histopathology

DOI: 10.1309/CCR3QN4874YJDJJ7

A b s t r a c t

Neoadjuvant chemoradiotherapy is beingincreasingly offered to patients with invasiveesophageal carcinoma in an effort to downstage thetumor and consequently increase the rate of curativeresection. A substantial amount of data has suggestedthat pathologic tumor regression following neoadjuvanttherapy is an important predictor of local recurrenceand long-term survival in esophageal cancer. Therefore,it is important that these posttreatment resectionspecimens are handled in a standardized manner and areproducible method of tumor regression grading isused. Pathologic examination of such specimens is notstraightforward, and, in fact, it presents a particularchallenge to pathologists, especially when a goodresponse to neoadjuvant therapy has been achieved andlittle or no residual tumor remains. We provide someguidelines for handling and reporting such specimensand outline the commonly used tumor regressiongrading systems for posttreatment esophagectomyspecimens.

Esophageal carcinoma ranks among the 10 most frequentmalignancies worldwide.1,2 The 5-year survival rate from diag-nosis for these patients is low, about 10%.2-5 In the past decade,the incidence of adenocarcinoma of the lower esophagus andgastroesophageal junction has risen markedly, and it is nowmore common than squamous cell carcinoma in the UnitedKingdom and United States.6,7 Attempts have been made to usepreoperative chemoradiotherapy to downstage the primarytumor and destroy occult lymph node metastases to increase thepossibility of a successful complete resection and to decreasethe rate of tumor recurrence.8-18 Meta-analyses of randomizedtrials of neoadjuvant treatment in patients with esophageal can-cer to date have shown that the degree of benefit is substantialand highly comparable with the benefits of neoadjuvant treat-ment in other cancers, such as breast, colorectal, and lung.19-21

At present, there is no clinical imaging modality that canaccurately gauge tumor response to chemoradiation, andpathologic examination of the posttreatment resection speci-men remains the gold standard for evaluation of tumorresponse.22 There has been accumulating evidence to suggestthat pathologic responses in the tumor to primary therapy areimportant predictors of local recurrence and long-term sur-vival.23-29 Therefore, preoperative neoadjuvant therapy hasbeen used increasingly in the management of this group ofpatients, and many esophageal carcinoma resection specimensarrive at the laboratory already modified by chemoradiation.Pathologic examination of such specimens may be difficult,particularly if there has been a good response to preoperativeneoadjuvant therapy; even the site of the cancer may be diffi-cult to identify macroscopically and microscopically.

We present a brief review of the literature on morpholog-ic changes associated with preoperative neoadjuvant therapy

Am J Clin Pathol 2008;129:252-262 253253 DOI: 10.1309/CCR3QN4874YJDJJ7 253


Anatomic Pathology / REVIEW ARTICLE

and outline the most commonly used tumor regression grad-ing (TRG) systems. Special issues regarding specimen pro-cessing and histopathologic examination of posttreatmentesophagectomy specimens are also discussed.

Chemoradiotherapy-Induced MorphologicChanges

It is well known that chemoradiotherapy causes a numberof histopathologic changes in the tumor and its adjacent tissueTable 1.23-30

Changes in Tumor CellsMarked cytoplasmic eosinophilia and vacuolation are

commonly seen Image 1. There is often associated nuclearatypia without apparent mitotic activity.30 When little residual

tumor remains, carcinoma cells are often dissociated andarranged singly, in short lines or tubules in a fibrotic stroma.Carcinoma cells may have very large nuclei, often bizarrelyshaped and multilobated. Nuclear chromatin in tumor cellstends to be vesicular with large eosinophilic single or multiplenucleoli. The culmination of these changes is often upgradingof the tumor to a poorly differentiated carcinoma.

The percentage of tumor cells with neuroendocrine dif-ferentiation seems to increase in posttreatment resection spec-imens Image 2. Morphologically, this can encompass the fullrange of the neuroendocrine spectrum, from large cells withabundant granular eosinophilic cytoplasm to poorly differenti-ated small round carcinoma cells resembling small cell carcino-ma, but immunophenotypic expression of neuroendocrine mark-ers is required for confirmation. Neuroendocrine change wasfound in 52% of residual adenocarcinomas after preoperative

Table 1Neoadjuvant TherapyInduced Morphologic Changes in Tumor Cells and Nonneoplastic TissueMorphologic Changes Description

In tumor cellsArchitecture Dissociated tubules, short lines, or single cells in a fibrotic stroma; discohesive cells, often suspended in pools

of mucin in mucinous tumorsNucleus Nuclear membrane irregularities; chromatin clumping, including pyknosis, karyorrhexis, and formation of

apoptotic bodies; may have large and bizarrely shaped nuclei with multiple lobes and popcorn-like appearance; fewer mitotic figures; large, often multiple nucleoli

Cytoplasm Dense, granular and eosinophilic, or vacuolated; may have merging of cytoplasm of adjacent cellsIn nonneoplastic tissue

Blood vessels Intimal proliferation, telangiectasia, organizing thrombi and endarteritis obliterans; atypical endothelial proliferation also possibly present

Stroma Transmural fibrosis and elastosis with a lymphoplasmacytic chronic inflammatory cell infiltrate, bizarre fibroblasts, foreign body reaction

Epithelial changes Esophageal mucosa: may show squamous metaplasia and atrophy of submucosal glands; villiform change of squamous mucosa; gastric mucosa: may show atrophy of specialized glands and increased numbers of apoptotic bodies

A B

Image 1 Chemoradiotherapy-induced morphologic changes. Scattered pyknotic carcinoma cells are present in an inflammatoryfibrous stroma. Carcinoma cells show cytoplasmic eosinophilia and vacuolization (H&E, A, 200; B, 400).



Chang et al / ESOPHAGEAL CARCINOMAS AFTER CHEMORADIATION

neoadjuvant therapy, whereas such change was seen in only38% of the paired pretreatment biopsy specimens.31 Notably,the neuroendocrine component seems to be more resistant topreoperative neoadjuvant therapy than tumors without suchdifferentiation, and the presence of neuroendocrine differenti-ation in residual esophageal carcinomas has been associatedwith a worse clinical outcome.31

Stromal and Vascular ChangesTumor regression in posttreatment specimens seems to be

mostly in the form of fibrosis or fibroinflammatory changesreplacing tumor cells (Image 1).30 Mucinous substance infibrotic areas should not be considered as vital residual tumorbut rather a sign of therapeutic success. Bizarre stromalfibroblasts are often present. There are large, atypical endothe-lial cells in granulation tissue underlying ulcerated tumor.Vascular changes such as telangiectasia, organizing thrombi,myxohyaline intimal proliferation of vessels, and endarteritisobliterans are common. Giant cell reaction around ghost cellsand keratin may be seen in squamous cell carcinoma.

Nonneoplastic Epithelial ChangesChemoradiotherapy does not exclusively target the tumor

cells; it also has some effect on nonneoplastic tissues. The mor-phologic alterations seen, such as an increase in nuclear/cyto-plasmic ratio, nuclear pleomorphism, clumping of chromatin,and the presence of prominent, multiple, and irregular nucleoli,may cause confusion with dysplasia and carcinoma.

Acanthosis of squamous epithelium away from tumor,with exaggeration of surface folds giving a serrated appear-ance, may be present. Esophageal submucosal mucous glandsshow acinar atrophy and squamous metaplasia. Squamous

epithelium adjacent to tumor may show spongiosis, focalacantholysis, ballooning, and cystic degeneration of ke-ratinocytes. Specialized gastric mucosa shows focal glandatrophy, flattening of epithelium, and nuclear atypia.Apoptotic bodies may be seen in the parietal and chief cells.Gland lumina frequently contain neutrophils and cell debris.There is often a pronounced lymphoplasmacytic infiltrate inthe adjacent esophageal and gastric mucosa.

Tumor Regression Grading

On gross examination, posttreatment resection specimenscan be roughly divided into 3 macroscopic groups. In the firstgroup, there is bulky residual tumor with no evidence of grossresponse to preoperative neoadjuvant therapy. In the secondgroup, apparent tumor regression is present. No macroscopicresidual tumor is seen but a scar (tumor bed) is found instead.The third group includes partial-response cases in whichfibrosis and a variable amount of residual tumor are grosslypresent. However, accurate TRG relies on the microscopicassessment. So far, several classification systems have beenused to assess the pathologic response to preoperative neoad-juvant therapy Table 2,30,32-37 none of which has become uni-versally accepted.

The TRG system described by Mandard et al30 seems tobe the most widely used. This system estimates the percentageof residual carcinoma in relation to the total tumor area,including the amount of radiation-induced tissue injury. Thismethod distinguishes 5 tumor regression grades. TRG1 isdefined as the absence of residual tumor and fibrosis extend-ing through the different layers of the esophageal wall. TRG2

A B

Image 2 Neuroendocrine differentiation in residual esophageal carcinoma. A, Poorly differentiated carcinoma cells arranged incords and nests showing hyperchromatic nuclei and nuclear molding (H&E, 200). B, Tumor cells are positive for CD56 (400).




is characterized by rare residual cancer cells scatteredthroughout the fibrosis. TRG3 has more residual tumor cells,but fibrosis still predominates. In TRG4, residual cancer cellspredominate in the fibrosis, and in TRG5, the tumor shows nosigns of regression.

This TRG system has been shown to be reproducible byseveral authors.23,37 Esophagectomy specimens histologicallygraded as TRG1 or TRG2 have been associated with a statis-tically significant survival benefit compared with other regres-sion classes. However, no statistically significant differencecould be detected between pathologic complete remission(TRG1) and microscopic residual disease (TRG2) in patientswith esophageal cancer.30 Because the separation of TRG1from TRG2 tumors is dependent on the diligence of thepathologist in searching for scanty residual tumor cells, thisstatistical nonsignificance may be false.

In a large retrospective review of 235 cases carried out byChirieac et al,32 a 4-tiered classification scheme Image 3 forextent of residual carcinoma was used: 0% residual carcino-ma, 1% to 10% residual carcinoma, 11% to 50% residual car-cinoma, and more than 50% (gross residual carcinoma).Overall survival was best for patients with no residual carci-noma and worst for patients with more than 50% residual car-cinoma, but there was no statistical difference in survivalbetween patients with 1% to 10% and 11% to 50% residualcarcinoma, who were in an intermediate prognostic category.

On the basis of these results, Wu et al34 proposed a 3-tiered classification as P0 (0% residual carcinoma), P1 (1%-50% residual carcinoma), and P2 (>50% residual carcinoma)to reflect the status of tumor response to chemoradiation. The4- and 3-tiered grading systems were tested in 60 coded casesof esophageal adenocarcinomas treated with preoperativechemoradiation followed by esophagectomy. The cases werereviewed by 6 pathologists from 4 institutions for extent ofresidual carcinoma and pathologic TNM stage. Their results

suggested that the interobserver agreement for extent of resid-ual carcinoma is excellent when using a 3-tiered classificationscheme (all scores >0.75). Patients with 0% residual carci-noma (P0) had significantly better overall survival thanpatients with 1% to 50% residual carcinoma (P1) and patientswith more than 50% residual carcinoma (P2). Further subdi-viding the pathologic response in the P1 group into 1% to 10%residual carcinoma and 11% to 50% residual carcinoma wasnot highly reproducible and could achieve at best only goodagreement among pathologists ( = 0.62 for 1%-10% residualcarcinoma; = 0.50 for 11%-50% residual carcinoma).Therefore, this 3-tiered grading system seems to be more eas-ily implemented and more reproducible and yields similarquality prognostic information.

Pathologic complete response rates have been reported in upto 30% of patients.23-37 Most patients experience at least a partialresponse after preoperative neoadjuvant therapy. Although differ-ent neoadjuvant therapy regimens have been used for preopera-tive treatment of different carcinoma types, data have suggestedthat the TRG classifications could be equally applicable to squa-mous cell carcinoma and adenocarcinoma.26

Special Issues in Specimen Examinationand Reporting

As for conventional cancer resection specimens, all post-treatment esophagectomy specimens should be examined byexperienced surgical pathologists according to standardizedprotocols (eg, College of American Pathologists CancerProtocols and the Royal College of Pathologists MinimumDataset) that include World Health Organization tumor classi-fication, tumor differentiation, lymph node involvement,resection margin status, and TNM staging. The y symbolshould be used for staging following neoadjuvant chemora-diotherapy.38 The ypTNM categorizes the extent of residualtumor in posttreatment resection specimens; it is not an esti-mate of tumor before initiation of neoadjuvant therapy.38

Macroscopic ExaminationSpecimens should be sent immediately to the pathology

laboratory, ideally in the fresh state. If this is not possible, thespecimen should be fixed in formalin of a volume at leasttwice that of the specimen. The specimen should be accompa-nied by full clinical information, including the tumor site; thetumor type and grade if biopsied before neoadjuvant therapy;the type of neoadjuvant therapy; and the radiologic and clinicalassessments of the response to neoadjuvant therapy. Owing toneoadjuvant therapyinduced fibrosis, the esophagectomyspecimens may be of suboptimal quality and any tears ordefects in the esophageal adventitia or muscularis proprianeed to be carefully documented.

Table 2Tumor Regression Grading (TRG) Systems Commonly Usedin Gastroesophageal Carcinomas

5-tiered grading system proposed by Mandard et al30TRG 1, absence of residual cancer and extensive fibrosisTRG 2, rare residual cancer cells scattered through the fibrosisTRG 3, increased residual cancer cells but fibrosis still predominatingTRG 4, residual cancer outgrowing fibrosisTRG 5, absence of regressive changes

4-tiered grading system advocated by Chirieac et al,32 Brucher etal,25 Swisher et al,33 and Wu et al34

TRG 1, no residual carcinomaTRG 2, 1%-10% residual carcinomaTRG 3, 11%-50% residual carcinomaTRG 4, >50% residual carcinoma

3-tiered grading system advocated by Swisher et al,33 Malaisrie etal,27 and Wu et al34

P0, 0% residual tumorP1, 1%-50% residual tumorP2, >50% residual tumor




Specimens should be well fixed. The issue of whether theesophagus should be opened longitudinally and pinned or leftintact in the region of the tumor and the lumen stuffed with a

tissue paper wick is a contentious one.39 It is our opinion thatas long as the circumferential resection margin is inked beforecutting through it, a flexible approach should be adopted, with

3-Tiered

P0(0%)

P2(>50%)

P1(1-50%)

4-Tiered

TRG1(0%)

TRG4(>50%)

TRG2(1-10%)

TRG3(11-50%)

Image 3 Schematic diagram and representative illustrations for assessment of residual esophageal carcinoma inposttreatment resection specimens. In the 4-tiered tumor regression grading (TRG) system, the extent of residual carcinoma isclassified as 0% residual carcinoma (TRG1), 1% to 10% residual carcinoma (TRG2) (arrows), 11% to 50% residual carcinoma(TRG3), and >50% residual carcinoma (TRG4). The modified 3-tiered system is devised by combining TRG2 and TRG3 to form asingle category. (Modified from Wu et al.34)



noncircumferential and impalpable tumors best pinned andbulky circumferential tumors best left intact.

The sampling technique and the number of blocks takenare clearly dependent on the size of the residual tumor. In manyinstitutions, including ours, the fixed specimen is cut into com-plete transverse slices encompassing the entire area of tumorImage 4. Orientation of the sliced sections can be achieved byinking the quadrants of circumferential resection margin in dif-ferent colors. If the lesion remains macroscopically visible, thespecimen can be handled as a specimen not having receivedpreoperative therapy. A minimum of 4 paraffin blocks shouldbe taken from the tumor, including samples from its closestpoint to the nearest margin to enable microscopic assessment.In approximately one third of cases, the tumors may have com-plete or near complete response to preoperative therapy.Macroscopic assessment of these specimens can be difficult.The tumor may be ill-defined and impossible to distinguishfrom fibrous stromal tissue. In these cases, it is important toidentify the tumor bed. Characteristically, this is a central,sometimes somewhat edematous-appearing area of fibrosisImage 5. Pathologic complete response is the gold standardfor many of the ongoing clinical trials and is recognized to be agood prognostic factor for patients; pathologists must, there-fore, sample widely to confirm that there is indeed no patholog-ically detectable disease. If the tumor bed cannot be identifiedmacroscopically, the entire area of macroscopic abnormalitymay need to be blocked.

The Siewert classification of junctional adenocarcinomais used, as for tumors resected without previous neoadjuvanttherapy.40,41 Accordingly, adenocarcinoma of the distal esoph-agus with the center of the tumor lying 1 to 5 cm above the

gastroesophageal junction is designated as Siewert type 1,with the center of the tumor lying between 1 cm above and 2cm below the gastroesophageal junction is designated asSiewert type 2, and with the center of the tumor lying between2 and 5 cm below the gastroesophageal junction is designatedas Siewert type 3. This classification determines whichypTNM system should be used: Siewert type 1 adenocarcino-mas are considered as esophageal primary tumors, whereastype 2 and type 3 adenocarcinomas are regarded as gastric pri-mary tumors. Notably, carcinomas of the squamous, smallcell, and undifferentiated types located at the gastro-esophageal junction (topographically equivalent to Siewerttype 2 tumors) are classified as esophageal primary tumors. Incases with complete pathologic response, the location of thetumor bed determines the Siewert typing.

The use of large (mega) blocks Image 6, if available, canbe valuable in determining the distribution of residual tumorfoci, when present. If only patchy residual disease is presentand tumor is no longer contiguous, this can be identified par-ticularly clearly in such large blocks.

The documentation of the size, location, and grossappearance of the tumor as digital images is often useful in thereporting of the specimen and discussion of the case in corre-lation with radiologic images at multidisciplinary meetings.

Microscopic ExaminationA histologic complete pathologic response is defined by

the inability of the pathologist to demonstrate any viable (non-necrotic) tumor cells within the specimen. Microscopic evi-dence of a tumor bed must be identified, and this is mandato-ry for assessment of complete response. Histologically, the

A B

Image 4 A, An example of macroscopic examination of partial esophagogastrectomy specimen containing a Siewert type 2tumor at the gastroesophageal junction. B, After fixation, the specimen is transversely sectioned and the slices are laid out forinspection and blocking.





A B

C Image 5 Complete pathologic response. A, A tumor bed(arrow) with surface ulceration and transmural fibrosis ispresent, but no visible tumor is seen on macroscopicexamination. B, This area is composed of fibrous tissueinfiltrated by inflammatory cells (H&E, 100). C, Note the bloodvessels showing intimal hyperplasia (H&E, 200).

A B

Image 6 An example of a mega block section of esophageal carcinoma. A, A transversely sectioned slice revealing bulkyresidual tumor on macroscopic examination. B, The tumor apparently infiltrates into esophageal adventitial fibrofatty tissue andlies very close to the circumferential resection margin.



tumor bed is characterized by abnormal fibroblastic stromathat is devoid of the normal layers of the esophageal wall andcontains foamy macrophages and a moderate number offibroblasts and mononuclear inflammatory cells (Image 5). Inthese areas, there may be edema or mucinous or myxoidchange of the stroma or even areas of necrosis.

The presence of mucin lakes without associated malig-nant cells should be defined as a pathologic complete responseImage 7. Similarly, necrotic areas (Image 7) and keratinflakes without identifiable viable cancer cells should bedefined as a pathologic complete response.

When there is diagnostic uncertainty, step-sections andfurther staining procedures such as mucin staining (alcianblueperiodic acidSchiff) and immunohistochemical analy-sis for pancytokeratin (MNF116 or AE1/AE3) may be helpfulin distinguishing individual tumor cells from treatment-relat-ed bizarre fibroblasts and foreign body giant cells Image 8.

Lymph Node HandlingThe use of chemoradiotherapy seems to cause lymph

nodes to undergo regression and atrophy to such an extent thatthey may become impalpable macroscopically. Therefore, the

A B

A B

Image 7The presence of necrotic areas (A, H&E, 200) and mucin lakes (B, H&E, 400) without identifiable viable carcinomacells should be defined as a pathologic complete response.

Image 8 Good response to preoperative treatment is evident in this specimen. A, Only occasional residual carcinoma cells areseen, and a confident diagnosis is obscured by the presence of chemoradiation-induced bizarre fibroblasts and histiocyticmultinucleated giant cells (H&E, 400). B, Immunohistochemical analysis for pancytokeratin (MNF116) highlights the residualcarcinoma cells (400).





number of lymph nodes found following preoperative therapyis generally low. Careful searching for lymph nodes is essen-tial. In addition, random sampling of adventitial fat oftenyields only microscopically identifiable lymph nodes.

On microscopic examination, the lymph nodes usuallydisplay considerable lymphoid depletion, sinus histiocyto-sis, accumulation of hemosiderin-laden macrophages, fibro-sis, hyalinization, and acellular mucin lakes. As for the pri-mary tumor, these changes are regarded as negative forresidual tumor unless viable cancer cells can be demonstrat-ed. The residual metastatic carcinoma cells may show cyto-logic changes similar to those seen in the primary tumor.When little residual tumor remains, it may be impossible todemonstrate carcinoma cells in H&E-stained slides. The useof immunohistochemical analysis for broad-spectrumcytokeratins, such as MNF116 and AE1/AE3, may be help-ful in these cases Image 9. However, false-positive resultsmay occur, and assessment must be based on the correlationof such immunohistochemical findings with morphologicfeatures.

Pathology ReportIn addition to comment on the pathologic response to pre-

operative neoadjuvant therapy (ie, tumor regression grade),the histopathology report for posttreatment esophagectomyspecimens should also include the principal prognostic factorsalready being used for nontreated esophageal cancer speci-mens. These have been detailed in the CAP Cancer Protocols(available at http://www.cap.org) and the Royal College ofPathologists Minimum Dataset (available at http://www.rcpath.org). Briefly, a report should include comments on thetype and differentiation of the tumor, depth of invasion, TRG,

involvement of the resection margins, vascular and perineur-al invasion, and lymph node involvement.

Preoperatively treated esophageal tumors are gradedusing the same criteria as nontreated carcinomas.20-30 It isimportant to note that histologic grading of these treatedtumors may be affected by therapy-induced morphologicchanges. As discussed in the preceding sections, preoperativeneoadjuvant therapy causes a number of architectural andcytologic changes. These include increased percentage oftumor cells with neuroendocrine differentiation and increasednuclear atypia of residual cancer cells.30,31 The culmination ofthese changes could lead to upgrading of the tumor to a poor-ly differentiated carcinoma. Further evaluation of neoadjuvanttherapyinduced tumor morphologic changes and their possi-ble effects on tumor differentiation would be helpful in defin-ing more accurate tumor grading systems for preoperativelytreated esophageal carcinomas.

Conclusions and Future Direction

A substantial amount of data has been accumulated tosuggest that TRG and pathologic ypTNM staging are impor-tant prognostic factors in esophageal cancer.23-37 Althoughresponse to therapy has been evaluated using various radiolog-ic imaging techniques, currently, there is no clinical imagingmodality that can accurately gauge tumor response tochemoradiation,22,42 and pathologic examination of the resect-ed specimen remains the gold standard for tumor responseassessment.23-37 Therefore, it is important that these posttreat-ment resection specimens are handled in a standardized man-ner, and a reproducible TRG method must be used.

A B

Image 9 A, A lymph node shows extensive fibrosis (H&E, 100). B, Scattered carcinoma cells are identified byimmunostaining for pancytokeratin (MNF116) (100).



There is significant variability in the histopathologicresponse of tumors to neoadjuvant chemotherapy. Approximately15% to 30% of patients experience a complete response,whereas up to 70% of patients have an incomplete or noresponse to the neoadjuvant regimen. The identification offactors that predict a response would be of considerable clini-cal benefit. The underlying mechanism for this variability isunknown, and, currently, there are no reliable predictors ofresponse based on standard pathologic assessment andimmunohistochemical analysis of biopsy specimens.43

Contributing factors may include the diverse geneticalterations involved in growth factor receptors, chemokines ofangiogenesis, tumor suppressor genes, cell cycle regulatorsand enzymes involved in the DNA repair system, apoptosis,and the degradation of extracellular matrix.43-48 Preliminaryreports indicate that gene expression profiles and polymor-phisms seem to allow prediction of sensitivity to specificchemotherapy and radiotherapy regimens44,48 and, thus, mayallow rational and individualized treatment approaches forgastroesophageal carcinomas.

From the Department of Histopathology, St Thomas Hospital,Guys and St Thomas NHS Foundation Trust, London, England.

Address correspondence to Dr Chang: Dept ofHistopathology, St Thomas Hospital, Guys and St Thomas NHSFoundation Trust, Lambeth Palace Rd, London SE1 7EH, England.

Acknowledgment: The skillful technical assistance of K.Marsden, FIBMS, and R. Cumming, FIBMS, is gratefullyacknowledged.

References1. Jemal A, Murray T, Ward W, et al. Cancer statistics. CA

Cancer J Clin. 2005;55:10-30.2. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med.

2003;349:2241-2252.3. Hofstetter W, Swisher SG, Correa AM, et al. Treatment

outcomes of resected esophageal cancer. Ann Surg.2002;236:376-385.

4. Hagen JA, DeMeester SR, Peters JH, et al. Curative resectionfor esophageal adenocarcinoma: analysis of 100 en blocesophagectomies. Ann Surg. 2001;234:520-530.

5. Muller JM, Erasmi H, Stelzner M, et al. Surgical therapy ofoesophageal carcinoma. Br J Surg. 1990;77:845-857.

6. Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in theincidence of esophageal and gastric carcinoma in the UnitedStates. Cancer. 1998;83:2049-2053.

7. DeMeester SR. Adenocarcinoma of the esophagus and cardia:a review of the disease and its treatment. Ann Surg Oncol.2006;13:12-30.

8. Leichman L, Steiger Z, Seydel HG, et al. Preoperativechemotherapy and radiation therapy for patients with cancerof the esophagus: a potentially curative approach. J Clin Oncol.1984;2:75-79.

9. Forastiere AA, Orringer MB, Perez-Tamayo C, et al.Preoperative chemoradiation followed by transhiatalesophagectomy for carcinoma of the esophagus: final report.J Clin Oncol. 1993;11:1118-1123.

10. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapyfollowed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997;337:161-167.

11. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapyfollowed by surgery compared with surgery alone for localizedesophageal cancer. N Engl J Med. 1998;339:1979-1984.

12. Coia LR, Minsky BD, Berkey BA, et al. Outcome of patientsreceiving radiation for cancer of the esophagus: results of the1992-1994 Patterns of Care Study. J Clin Oncol. 2000;18:455-462.

13. Stein H, Sendler A, Ulrich F, et al. Multidisciplinary approachto esophageal and gastric cancer. Surg Clin North Am.2000;80:659-682.

14. Heath EI, Burtness BA, Heitmiller RF, et al. Phase II evaluationof preoperative chemoradiation and postoperative adjuvantchemotherapy for squamous cell and adenocarcinoma of theesophagus. J Clin Oncol. 2000;18:868-876.

15. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial ofpreoperative chemoradiation versus surgery alone in patientswith locoregional esophageal carcinoma. J Clin Oncol.2001;19:305-313.

16. Ancona E, Ruol A, Santi S, et al. Only pathologic completeresponse to neoadjuvant chemotherapy improves significantlythe long term survival of patients with resectable esophagealsquamous cell carcinoma. Cancer. 2001;91:2165-2174.

17. Medical Research Council Oesophageal Cancer WorkingGroup. Surgical resection with or without preoperativechemotherapy in oesophageal cancer: a randomised controlledtrial. Lancet. 2002;359:1727-1734.

18. Meluch AA, Greco FA, Gray JR, et al. Preoperative therapywith concurrent paclitaxel/carboplatin/infusional 5-FU andradiation therapy in locoregional esophageal cancer; finalresults of a Minnie Pearl Cancer Research Network phase IItrial. Cancer J. 2003;9:251-260.

19. Gebski V, Burmeister B, Smithers BM, at el. Survival benefitsfrom neoadjuvant chemoradiotherapy or chemotherapy inoesophageal carcinoma: a meta-analysis. Lancet Oncol.2007;8:226-234.

20. Greil R, Stein HJ. Is it time to consider neoadjuvant treatmentas the standard of care in oesophageal cancer [letter]? LancetOncol. 2007;8:189-190.

21. Schneider BJ, Urba SG. Preoperative chemoradiation for thetreatment of locoregional esophageal cancer: the standard ofcare? Semin Radiat Oncol. 2007;17:45-52.

22. Westerterp M, van Westreenen HL, Reitsma JB, et al.Esophageal cancer: CT, endoscopic US, and FDG PET forassessment of response to neoadjuvant therapy: systematicreview. Radiology. 2005;236:841-851.

23. Dunne B, Reynolds JV, Mulligan E, et al. A pathological study oftumour regression in oesophageal adenocarcinoma treated withpreoperative chemoradiotherapy. J Clin Pathol. 2001;54:841-845.

24. Brucher BL, Stein HJ, Zimmermann F, et al. Respondersbenefit from neoadjuvant radiochemotherapy in esophagealsquamous cell carcinoma: results of a prospective phase-II trial.Eur J Surg Oncol. 2004;30:963-971.

25. Brucher BL, Becker K, Lordick F, et al. The clinical impact of histopathologic response assessment by residual tumor cellquantification in esophageal squamous cell carcinomas.Cancer. 2006;106:2119-2127.

26. Schneider PM, Baldus SE, Metzger R, et al. Histomorphologictumor regression and lymph node metastases determineprognosis following neoadjuvant radiochemotherapy foresophageal cancer: implications for response classification.Ann Surg. 2005;242:684-692.





27. Malaisrie SC, Hofstetter WL, Correa AM, et al. The additionof induction chemotherapy to preoperative, concurrentchemoradiotherapy improves tumor response in patients withesophageal adenocarcinoma. Cancer. 2006;107:967-974.

28. Korst RJ, Kansler AL, Port JL, et al. Downstaging of T or Npredicts long-term survival after preoperative chemotherapyand radical resection for esophageal carcinoma. Ann ThoracSurg. 2006;82:480-485.

29. de Manzoni G, Pedrazzani C, Pasini F, et al.Chemoradiotherapy followed by surgery for squamous cellcarcinoma of the thoracic esophagus with clinical evidence of adjacent organ invasion. J Surg Oncol. 2007;95:261-266.

30. Mandard AM, Dalibard F, Mandard JC, et al. Pathologicassessment of tumor regression after preoperativechemoradiotherapy of esophageal carcinoma;clinicopathologic correlations. Cancer. 1994;73:2680-2686.

31. Hornick JL, Farraye FA, Odze RD. Prevalence and significanceof prominent mucin pools in the esophagus post neoadjuvantchemoradiotherapy for Barretts-associated adenocarcinoma.Am J Surg Pathol. 2006;30:28-35.

32. Chirieac LR, Swisher SG, Ajani JA, et al. Posttherapypathologic stage predicts survival in patients with esophagealcarcinoma receiving preoperative chemoradiation. Cancer.2005;103:1347-1355.

33. Swisher SG, Hofstetter W, Wu TT, et al. Proposed revision ofthe esophageal cancer staging system to accommodatepathologic response (pP) following preoperativechemoradiation (CRT). Ann Surg. 2005;241:810-820.

34. Wu TT, Chirieac LR, Abraham SC, et al. Excellentinterobserver agreement on grading the extent of residualcarcinoma after preoperative chemoradiation in esophagealand esophagogastric junction carcinoma: a reliable predictorfor patient outcome. Am J Surg Pathol. 2007;31:58-64.

35. Wang KL, Yang Q, Cleary KR, et al. The significance ofneuroendocrine differentiation in adenocarcinoma of theesophagus and esophagogastric junction after preoperativechemoradiation. Cancer. 2006;107:1467-1474.

36. Hermann RM, Horstmann O, Haller F, et al.Histomorphological tumor regression grading of esophagealcarcinoma after neoadjuvant radiochemotherapy: which scoreto use? Dis Esophagus. 2006;19:329-334.

37. MacGuill M, Mulligan E, Ravi N, et al. Clinicopathologicfactors predicting complete pathological response toneoadjuvant chemoradiotherapy in esophageal cancer. DisEsophagus. 2006;19:273-276.

38. Sobin LH, Wittekind CH, International Union AgainstCancer, eds. TNM Classification of Malignant Tumours. 5th ed.Baltimore, MD: Wiley-Liss, 1997.

39. Ibrahim NB. Guidelines for handling oesophageal biopsies and resection specimens and their reporting. J Clin Pathol.2000;53:89-94.

40. Stein HJ, Feith M, Siewert JR. Cancer of the esophagogastricjunction. Surg Oncol. 2000;9:35-41.

41. Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg. 1998;85:1457-1459.

42. Forshaw MJ, Gossage JA, Mason RC. Neoadjuvantchemotherapy for oesophageal cancer: the need for accurateresponse prediction and evaluation. Surgeon. 2005;3:373-382,422.

43. Vallbohmer D, Lenz HJ. Predictive and prognostic molecularmarkers in outcome of esophageal cancer. Dis Esophagus.2006;19:425-432.

44. Wieder HA, Brcher BL, Zimmermann F, et al. Time course of tumor metabolic activity during chemoradiotherapy ofesophageal squamous cell carcinoma and response totreatment. J Clin Oncol. 2004;22:900-908.

45. Heeren PA, Kloppenberg FW, Hollema H, et al. Predictiveeffect of p53 and p21 alteration on chemotherapy responseand survival in locally advanced adenocarcinoma of theesophagus. Anticancer Res. 2004;24:2579-2583.

46. Schneider S, Uchida K, Brabender J, et al. Downregulation ofTS, DPD, ERCC1, GST-Pi, EGFR, and HER2 gene expressionafter neoadjuvant three-modality treatment in patients withesophageal cancer. J Am Coll Surg. 2005;200:336-344.

47. Kaur T, Khanduja KL, Kaushik T, et al. P53, COX-2, iNOSprotein expression changes and their relationship with anti-oxidant enzymes in surgically and multi-modality treatedesophageal carcinoma patients. J Chemother. 2006;18:74-84.

48. Wu X, Gu J, Wu TT, et al. Genetic variations in radiation andchemotherapy drug action pathways predict clinical outcomesin esophageal cancer. J Clin Oncol. 2006;24:3789-3798.

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