Residual carcinoma cells after chemoradiotherapy for esophageal squamous cell carcinoma patients: striving toward appropriate judgment of biopsy

Residual carcinoma cells after chemoradiotherapy for esophageal squamous cell carcinoma patients:... Summary In esophageal squamous cell carcinoma (ESCC) patients who are treated with chemoradiotherapy (CRT), identification of the presence or absence of residual or recurrent carcinoma is usually pivotal in their clinical management. In addition, the extent of carcinoma invasion into the esophageal wall could determine the clinical outcome of these patients following CRT. Therefore, in this study, we evaluated the response to CRT both macroscopically and histologically in a consecutive series of 42 ESCC patients receiving neoadjuvant chemoradiotherapy following curative esophageal resection at Tohoku University Hospital between August 2011 and December 2012. The histological grading of tumor regression was as follows: grade 3, markedly effective (no viable residual tumor cells); grade 2, moderately effective (residual tumor cells in less than one-third of the tumor); grade 1, slightly effective (1b, residual tumor cells in one-third to two-thirds of the tumor; 1a, residual tumor cells in more than two-thirds of the tumor); and grade 0, ineffective. In this study, we selected grade 2 and 1b cases because they might show a complete response with definitive CRT. We evaluated the presence of any residual in situ lesions and tumor depth in detail. The grading of tumor regression in primary sites was as follows: grade 3 (7 cases), grade 2 (16 cases), grade 1b (13 cases), and grade 1a (6 cases). The concordance rate between macroscopic and histopathological evaluation on the depth of the tumor was 40% (17/42). Among 29 cases (grade 2 and grade 1b), intraepithelial lesions were not detected in 17 cases, and tumor nests were not detected in the lamina propria mucosae in 9 cases. The results of this study highlight the difficulties of detecting residual carcinoma cells using conventional endoscopic biopsy in patients who have received CRT. Therefore, when residual cancer is clinically suspected in patients who have received CRT, the biopsy specimen should be obtained from the deep layer of the esophagus whenever possible. Additionally, close follow-up is required using positron emission tomography/computed tomography, endoscopy, and other radiological evaluations. INTRODUCTION Chemoradiotherapy (CRT) is an established treatment for esophageal cancer and has demonstrated a relatively good treatment outcome, especially in squamous cell carcinoma patients.1 However, more than half of CRT-treated esophageal squamous cell carcinoma (ESCC) patients do not respond to treatment and subsequently require additional treatment, such as surgery or chemotherapy. The response to CRT is usually evaluated using biopsy in clinical management; however, discrepancies between biopsy results and clinical findings in terms of the presence or absence of residual carcinoma have been very frequently encountered in clinical practice. Esophageal cancer, especially ESCC, is well known to recur in multiple areas of the esophagus.2 Therefore, even though carcinoma cells appear to completely disappear following CRT, squamous cell carcinoma could occur in areas in which cancer was not clinically detected before therapy. In the great majority of such cases, the new lesions usually arise as intraepithelial carcinoma and are relatively easy to diagnose using endoscopic biopsy. They can also be completely cured using endoscopic resection.3,4 However, recurrent lesions can develop in relatively deep areas of the esophagus without concomitant intraepithelial squamous lesions.5 In order to treat these patients using additional therapeutic modalities, pathological evidence of residual carcinoma is usually required. Therefore, therapy is sometimes delayed until a definitive diagnosis or histological evidence of residual carcinoma can be acquired. However, results of previous studies have demonstrated that the prognosis of patients who underwent salvage surgery after being diagnosed with a clinical complete response is considerably better than that of patients undergoing the procedure after a diagnosis of residual cancer.6,7 Therefore, it is pivotal to diagnose such cancer recurrence as early as possible to provide the maximum opportunity for additional treatment, such as salvage esophagectomy. It is generally common to use endoscopy and computed tomography (CT) to determine the effect of CRT; however, endoscopic biopsy may not necessarily be the best modality to diagnose a pathological complete response in ESCC patients treated with CRT. For example, Sarkaria et al. reported that the negative predictive value of a pathological complete response was at best 31% for all esophageal cancer patients who were treated using CRT and underwent surgical resection after biopsy.8 Yamamoto et al. also reported difficulties in evaluating residual tumors after CRT because of the presence of small amounts of residual tumor underneath the mucosa.5 Shaukat et al. reported that endoscopy was unreliable for excluding residual disease in these patients.9 van Rossum et al. recently concluded that endoscopic biopsy following neoadjuvant CRT is a specific but not necessarily sensitive method for detecting residual esophageal cancer.10 These reports showed that more than two-thirds of patients had residual cancer, even though their biopsy results were negative. However, the reasons why we could not detect carcinoma cells using biopsy after CRT and the difficulties of interpreting the biopsy findings have not been studied in detail. Furthermore, appropriate methods to accurately detect residual carcinoma remain unknown. It is also important to note that, in addition to the presence or absence of carcinoma, the depth and extent of residual carcinoma could also profoundly influence the clinical outcome of patients who receive CRT. We performed this study to provide appropriate information regarding the risks and limitations of evaluating ESCC based only on biopsy findings. This is particularly important to reduce the incidence of patients diagnosed with recurrence at an advanced stage. We examined consecutive neoadjuvant CRT cases following curative esophagectomy and a diagnosis of ESCC with the same time period since the same CRT regimen. Furthermore, we evaluated the precise area of residual carcinoma cells in ESCC patients following CRT. We also compared the macroscopic findings with those of residual carcinoma in the surgical specimens and explored the diagnostic utility of biopsy evaluation. MATERIALS AND METHODS Patients A consecutive series of 42 patients underwent neoadjuvant chemoradiotherapy (NACRT) for ESCC followed by curative esophagectomy at the Tohoku University Hospital (Sendai, Japan) between August 2011 and December 2012. The NACRT protocol was based on the half dose of the definitive CRT protocol of the Japan Clinical Oncology Group (JCOG 9906) trial. In brief, the protocol consisted of 1 cycle of an intravenous infusion of cisplatin (40 mg/m2) on days 1 and 8 and a continuous infusion of 5-fluorouracil (400 mg/m2) over 24 h on days 1–5 and 8–12. Concurrent radiotherapy of 30 Gy was applied in 15 fractions over 3 weeks. At the end of NACRT, we performed endoscopy and aimed to evaluate the measurements of primary lesions as precisely as possible under magnified endoscopic evaluation. These endoscopic findings were carefully evaluated by Y.T and T.K who are highly trained in endoscopy and have gained sufficient experience over more than 10 years to evaluate esophageal cancer patients after NACRT or definitive CRT. Surgery was performed 4 weeks after the completion of NACRT. Response evaluation The response to CRT was evaluated both macroscopically and histopathologically. Endoscopic evaluation was performed in the period before NACRT and surgery. Both evaluations were performed using conventional white light and narrow band imaging (NBI). Lugol's staining and subsequent biopsy were performed before NACRT but not before surgery. Macroscopic evaluation was performed using the findings of the endoscopy and resected specimens, and histological evaluation was based on the Japanese Classification of Esophageal Cancer, 11th edition.2,11 We serially cross-sectioned the specimens at 0.5-cm intervals for entire lesion when the tumor remained, or for the lesion in which the tumor was assumed to be present before NACRT. Careful histological evaluation was performed (Fig. 1, case 22). The pathological stage of each cancer was defined according to the Union for International Cancer Control (UICC) TNM (tumor, node, metastasis) classification (7th edn.) system.12 The grading of tumor regression was based on an estimation of the percentage of viable tumor tissue in relation to the tumor bed as follows: grade 3, markedly effective (no viable residual tumor cells); grade 2, moderately effective (less than one-third residual tumor cells); grade 1, slightly effective (1b, one-third to two-thirds residual tumor cells; 1a, more than two-thirds residual tumor cells); and grade 0, ineffective (no therapeutic effect observed).2,6,12 Histopathological evaluation was performed by three pathologists (F.F., H.O., and Y.O.). In this study, we selected grade 2 and 1b cases because they might show a complete response to definitive CRT. We evaluated the presence of residual in situ lesions and residual tumor depth in these cases. In addition, we compared endoscopic or postoperative macroscopic evaluation with these clinicopathological parameters in individual patients. Fig. 1 View largeDownload slide The sectioning procedure for grade 2 disease (case no. 22). Specimens were serially cross-sectioned at 0.5-cm intervals where the entire lesion assumed to be the tumor was present before neoadjuvant chemoradiotherapy (NACRT). Fig. 1 View largeDownload slide The sectioning procedure for grade 2 disease (case no. 22). Specimens were serially cross-sectioned at 0.5-cm intervals where the entire lesion assumed to be the tumor was present before neoadjuvant chemoradiotherapy (NACRT). RESULTS Histopathological evaluation Among the 42 patients who received NACRT, five achieved a complete response by the time of surgery; namely, no residual tumor cells were detected in the esophagus or lymph nodes following extensive histopathological evaluation. In addition, two cases demonstrated a complete pathological response in the primary lesions but harbored residual carcinoma cells in the lymph nodes. Evaluation of tumor regression was performed in each case and the distribution was as follows: grade 3 (7 cases), grade 2 (16 cases), grade 1b (13 cases), and grade 1a (6 cases) (Table 1). We conducted pathological evaluation of 29 patients (grade 2 and grade 1b). Table 1 Cases characteristics: grading and pathological evaluation Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 †≧SM, invasion deeper than the submucosa (SM); ‡≧MP: invasion deeper than the muscularis propria (MP). View Large Table 1 Cases characteristics: grading and pathological evaluation Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 †≧SM, invasion deeper than the submucosa (SM); ‡≧MP: invasion deeper than the muscularis propria (MP). View Large Comparison between histological and macroscopic findings Among the 42 patients, the concordance rate of predictive depth between macroscopic and histopathological examination in the resected specimen was 40% (17/42). In 7 cases evaluated as T0 following macroscopic evaluation of the resected specimens, only 3 were pathologically defined as T0 based on the primary lesion. Four cases were determined to be pathologically T0, even though the presence of residual carcinoma was macroscopically suspected (Table 2). Table 2 Correlation between macroscopic and pathological findings (n = 42) Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 View Large Table 2 Correlation between macroscopic and pathological findings (n = 42) Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 View Large Intraepithelial lesion and location of tumor nests in the wall following CRT Twenty-nine cases were evaluated as grade 1b or 2. Among these 29 cases, no intraepithelial lesions were detected in 17 cases, even following detailed histopathological examination. In 12 cases harboring intraepithelial lesions, the horizontal length of the total intraepithelial lesion was less than 5 mm in 7 cases (Fig. 2, case 16). The locations of residual tumor nests in the esophageal wall of the grade 1b or 2 cases are summarized in Table 1. In nine cases, tumor nests were detected in the submucosa or muscularis propria, but were not detected in the layer above the submucosa (Fig. 3, case 22). Fig. 2 View largeDownload slide Characteristic residual pattern of mucosa (case no 16). The grading of tumor regression is 1b (A). The pathological findings indicated a residual tumor and the total intraepithelial lesion was 4 mm (B). The intraepithelial lesion is shown by the white line in A and the two arrows in B (hematoxylin and eosin staining). Fig. 2 View largeDownload slide Characteristic residual pattern of mucosa (case no 16). The grading of tumor regression is 1b (A). The pathological findings indicated a residual tumor and the total intraepithelial lesion was 4 mm (B). The intraepithelial lesion is shown by the white line in A and the two arrows in B (hematoxylin and eosin staining). Fig. 3 View largeDownload slide Macroscopic and microscopic findings of grade 2 disease (case No 22). Tumor nests were observed in only 2 areas (red points) (A). Pathological findings of residual tumor nests in muscularis propria and adventitia, respectively. The white arrow in the left upper panel in (A) and the yellow arrow in the left lower panel in (A). The panels on the right are the high-magnification versions of the panels on the left (B) (hematoxylin and eosin staining). Fig. 3 View largeDownload slide Macroscopic and microscopic findings of grade 2 disease (case No 22). Tumor nests were observed in only 2 areas (red points) (A). Pathological findings of residual tumor nests in muscularis propria and adventitia, respectively. The white arrow in the left upper panel in (A) and the yellow arrow in the left lower panel in (A). The panels on the right are the high-magnification versions of the panels on the left (B) (hematoxylin and eosin staining). DISCUSSION In this study, we evaluated 42 esophageal cancer patients who received CRT after undergoing esophageal resection. The results revealed that in the majority of grade 2 or grade 1b cases that responded to the therapy, intraepithelial lesions were not present or were only present in very small areas. In addition, carcinoma cells were not present above the submucosa in nine cases (31%). In those cases, endoscopic biopsy did not detect residual carcinoma cells, even when the procedure was performed by experienced endoscopists. These patients were considered to have a relapse of ESCC following a pathological complete response when tumors were clinically detected. Sometimes even salvage therapy, such as esophagectomy or other clinical modalities, could not improve the clinical outcome of these patients. Endoscopic biopsy cannot detect the presence of deep lesions. Therefore, patients harboring these lesions, especially those that are relatively small, have been erroneously diagnosed with a complete pathological response. This could be clinically critical for these patients, because they might miss the chance to receive further treatment, such as salvage esophagectomy. However, early clinical detection of cancer recurrence after a complete response to CRT can be very difficult. Practically, not only was the concordance rate of predictive depth between macroscopic and histopathological examination in the resected specimen low (about 40%), but in a few cases, we also made the wrong decision about whether carcinoma cells were residual or not. In addition, there is no definitive evidence regarding the appropriate timing of response evaluation and follow-up; therefore, patients diagnosed with a complete response to definitive CRT based on macroscopic endoscopic findings, as well as those of endoscopic biopsy, tend not to receive very close follow-up.13 Our study demonstrated that small cancer nests could be present under the submucosal layer, even in cases diagnosed as a clinical complete response. In those cases, cancer recurred inside the esophageal wall. However, the prognosis of patients diagnosed with a clinical complete response is considerably better than that of those diagnosed with residual cancer.6,7 Therefore, we believe that early detection of cancer recurrence is very important for additional treatment, such as salvage esophagectomy. Approximately half of patients who undergo definitive CRT develop a complete response and the esophagus is preserved; thus, definitive CRT is clearly a useful therapy.14 It is therefore essential to redesign the clinical algorithm in patients receiving CRT who are diagnosed with a clinical complete response after completion of the treatment; this will allow the detection of lesions that cannot be identified using routine endoscopic evaluation and biopsy. In addition, it is also important to clinically identify cases in which carcinoma cells disappear from the primary lesions but remain in the lymph nodes. Therefore, further examinations are necessary, such as the development of more refined endoscopic ultrasonography that could detect these lesions even when nonpathological endoscopic findings are obtained. In conclusion, pathologically negative cancer cells from ordinal biopsy are not reliable to diagnose esophageal cancer patients treated with CRT. If residual cancer is suspected based on the results of clinical modalities, such as endoscopy or PET/CT, close and repeated follow-up or total judgment is needed. This should be considered by every clinician and endoscopist involved in the clinical management of ESCC patients treated with CRT. ACKNOWLEDGMENTS We would like to thank Editage (www.editage.jp) for English language editing. Notes Specific author contributions: Fumiyoshi Fujishima and Yusuke Taniyama designed the study; Fumiyoshi Fujishima, Hiroshi Okamoto, Yohei Ozawa, Ken Ito, Hirotaka Ishida, and Takuro Konno-Kumagai collected the clinical information of the cases as needed; Fumiyoshi Fujishima, Hiroshi Okamoto, Yohei Ozawa diagnosed and evaluated the response of CRT; and Fumiyoshi Fujishima and Yusuke Taniyama mainly drafted the manuscript with some help from Yasuhiro Nakamura, Atsuko Kasajima, and Hironobu Sasano. All authors approved the final submitted version of the manuscript. Fumiyoshi Fujishima and Yusuke Taniyama contributed equally to this work. References 1 Ariga H , Nemoto K , Miyazaki S et al. Prospective comparison of surgery alone and chemoradiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus . Int J Radiat Oncol Biol Phys 2009 ; 75 : 348 – 56 . Google Scholar CrossRef Search ADS PubMed 2 Japan Esophageal Society . Japanese Classification of Esophageal Cancer, 11th Edition: part I . Esophagus 2017 ; 14 : 1 – 36 . CrossRef Search ADS PubMed 3 Kuwano H , Nishimura Y , Oyama T et al. Guidelines for diagnosis and treatment of carcinoma of the esophagus April 2012 edited by the Japan Esophageal Society . Esophagus 2015 ; 12 : 1 – 30 . Google Scholar CrossRef Search ADS PubMed 4 Nakamura R , Omori T , Takeuchi H et al. Salvage endoscopic resection as a treatment for locoregional failure or recurrence following chemoradiotherapy or radiotherapy for esophageal cancer . Oncol Lett 2016 ; 11 : 3631 – 36 . Google Scholar CrossRef Search ADS PubMed 5 Yamamoto M , Doki Y , Shiozaki H et al. Evaluation of the histologic effect of chemoradiation therapy for squamous cell carcinomas of the esophagus by assessing morphologic features of surgical specimens . Dis Esophagus 2000 ; 13 : 293 – 300 . Google Scholar CrossRef Search ADS PubMed 6 Okamoto H , Fujishima F , Nakamura Y et al. Murine double minute 2 and its association with chemoradioresistance of esophageal squamous cell carcinoma . Anticancer Res 2013 ; 33 : 1463 – 71 . Google Scholar PubMed 7 Wang S , Tachimori Y , Hokamura N et al. Prognostic analysis of salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous cell carcinoma: the importance of lymphadenectomy . J Thorac Cardiovasc Surg 2014 ; 147 : 1805 – 11 . Google Scholar CrossRef Search ADS PubMed 8 Sarkaria I S , Rizk N P , Bains M S et al. Post-treatment endoscopic biopsy is a poor predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer . Ann Surg 2009 ; 249 : 764 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Shaukat A , Mortazavi A , Demmy T et al. Should preoperative, post-chemoradiotherapy endoscopy be routine for esophageal cancer patients? Dis Esophagus 2004 ; 17 : 129 – 35 . Google Scholar CrossRef Search ADS PubMed 10 van Rossum P S , Goense L , Meziani J et al. Endoscopic biopsy and EUS for the detection of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer: a systematic review and meta-analysis . Gastrointest Endosc 2016 ; 83 : 866 – 79 . Google Scholar CrossRef Search ADS PubMed 11 Japan Esophageal Society . Japanese Classification of Esophageal Cancer, 11th Edition: part II and III . Esophagus 2017 ; 14 : 37 – 65 . CrossRef Search ADS PubMed 12 Sobin L H , Gospodarowicz M K , Wittekind C . UICC International Union Against . Cancer TNM Classification of Malignant Tumors , 7th ed . New York : Wiley-Blackwell ; 2009 . 13 Toh Y , Kitagawa Y , Kuwano H et al. A nation-wide survey of follow-up strategies for esophageal cancer patients after a curative esophagectomy or a complete response by definitive chemoradiotherapy in Japan . Esophagus 2016 ; 13 : 173 – 81 . Google Scholar CrossRef Search ADS 14 Okamoto H , Fujishima F , Kamei T et al. Murine double minute 2 predicts response of advanced esophageal squamous cell carcinoma to definitive chemoradiotherapy . BMC Cancer 2015 ; 15 : 208 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Residual carcinoma cells after chemoradiotherapy for esophageal squamous cell carcinoma patients: striving toward appropriate judgment of biopsy

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Abstract

Summary In esophageal squamous cell carcinoma (ESCC) patients who are treated with chemoradiotherapy (CRT), identification of the presence or absence of residual or recurrent carcinoma is usually pivotal in their clinical management. In addition, the extent of carcinoma invasion into the esophageal wall could determine the clinical outcome of these patients following CRT. Therefore, in this study, we evaluated the response to CRT both macroscopically and histologically in a consecutive series of 42 ESCC patients receiving neoadjuvant chemoradiotherapy following curative esophageal resection at Tohoku University Hospital between August 2011 and December 2012. The histological grading of tumor regression was as follows: grade 3, markedly effective (no viable residual tumor cells); grade 2, moderately effective (residual tumor cells in less than one-third of the tumor); grade 1, slightly effective (1b, residual tumor cells in one-third to two-thirds of the tumor; 1a, residual tumor cells in more than two-thirds of the tumor); and grade 0, ineffective. In this study, we selected grade 2 and 1b cases because they might show a complete response with definitive CRT. We evaluated the presence of any residual in situ lesions and tumor depth in detail. The grading of tumor regression in primary sites was as follows: grade 3 (7 cases), grade 2 (16 cases), grade 1b (13 cases), and grade 1a (6 cases). The concordance rate between macroscopic and histopathological evaluation on the depth of the tumor was 40% (17/42). Among 29 cases (grade 2 and grade 1b), intraepithelial lesions were not detected in 17 cases, and tumor nests were not detected in the lamina propria mucosae in 9 cases. The results of this study highlight the difficulties of detecting residual carcinoma cells using conventional endoscopic biopsy in patients who have received CRT. Therefore, when residual cancer is clinically suspected in patients who have received CRT, the biopsy specimen should be obtained from the deep layer of the esophagus whenever possible. Additionally, close follow-up is required using positron emission tomography/computed tomography, endoscopy, and other radiological evaluations. INTRODUCTION Chemoradiotherapy (CRT) is an established treatment for esophageal cancer and has demonstrated a relatively good treatment outcome, especially in squamous cell carcinoma patients.1 However, more than half of CRT-treated esophageal squamous cell carcinoma (ESCC) patients do not respond to treatment and subsequently require additional treatment, such as surgery or chemotherapy. The response to CRT is usually evaluated using biopsy in clinical management; however, discrepancies between biopsy results and clinical findings in terms of the presence or absence of residual carcinoma have been very frequently encountered in clinical practice. Esophageal cancer, especially ESCC, is well known to recur in multiple areas of the esophagus.2 Therefore, even though carcinoma cells appear to completely disappear following CRT, squamous cell carcinoma could occur in areas in which cancer was not clinically detected before therapy. In the great majority of such cases, the new lesions usually arise as intraepithelial carcinoma and are relatively easy to diagnose using endoscopic biopsy. They can also be completely cured using endoscopic resection.3,4 However, recurrent lesions can develop in relatively deep areas of the esophagus without concomitant intraepithelial squamous lesions.5 In order to treat these patients using additional therapeutic modalities, pathological evidence of residual carcinoma is usually required. Therefore, therapy is sometimes delayed until a definitive diagnosis or histological evidence of residual carcinoma can be acquired. However, results of previous studies have demonstrated that the prognosis of patients who underwent salvage surgery after being diagnosed with a clinical complete response is considerably better than that of patients undergoing the procedure after a diagnosis of residual cancer.6,7 Therefore, it is pivotal to diagnose such cancer recurrence as early as possible to provide the maximum opportunity for additional treatment, such as salvage esophagectomy. It is generally common to use endoscopy and computed tomography (CT) to determine the effect of CRT; however, endoscopic biopsy may not necessarily be the best modality to diagnose a pathological complete response in ESCC patients treated with CRT. For example, Sarkaria et al. reported that the negative predictive value of a pathological complete response was at best 31% for all esophageal cancer patients who were treated using CRT and underwent surgical resection after biopsy.8 Yamamoto et al. also reported difficulties in evaluating residual tumors after CRT because of the presence of small amounts of residual tumor underneath the mucosa.5 Shaukat et al. reported that endoscopy was unreliable for excluding residual disease in these patients.9 van Rossum et al. recently concluded that endoscopic biopsy following neoadjuvant CRT is a specific but not necessarily sensitive method for detecting residual esophageal cancer.10 These reports showed that more than two-thirds of patients had residual cancer, even though their biopsy results were negative. However, the reasons why we could not detect carcinoma cells using biopsy after CRT and the difficulties of interpreting the biopsy findings have not been studied in detail. Furthermore, appropriate methods to accurately detect residual carcinoma remain unknown. It is also important to note that, in addition to the presence or absence of carcinoma, the depth and extent of residual carcinoma could also profoundly influence the clinical outcome of patients who receive CRT. We performed this study to provide appropriate information regarding the risks and limitations of evaluating ESCC based only on biopsy findings. This is particularly important to reduce the incidence of patients diagnosed with recurrence at an advanced stage. We examined consecutive neoadjuvant CRT cases following curative esophagectomy and a diagnosis of ESCC with the same time period since the same CRT regimen. Furthermore, we evaluated the precise area of residual carcinoma cells in ESCC patients following CRT. We also compared the macroscopic findings with those of residual carcinoma in the surgical specimens and explored the diagnostic utility of biopsy evaluation. MATERIALS AND METHODS Patients A consecutive series of 42 patients underwent neoadjuvant chemoradiotherapy (NACRT) for ESCC followed by curative esophagectomy at the Tohoku University Hospital (Sendai, Japan) between August 2011 and December 2012. The NACRT protocol was based on the half dose of the definitive CRT protocol of the Japan Clinical Oncology Group (JCOG 9906) trial. In brief, the protocol consisted of 1 cycle of an intravenous infusion of cisplatin (40 mg/m2) on days 1 and 8 and a continuous infusion of 5-fluorouracil (400 mg/m2) over 24 h on days 1–5 and 8–12. Concurrent radiotherapy of 30 Gy was applied in 15 fractions over 3 weeks. At the end of NACRT, we performed endoscopy and aimed to evaluate the measurements of primary lesions as precisely as possible under magnified endoscopic evaluation. These endoscopic findings were carefully evaluated by Y.T and T.K who are highly trained in endoscopy and have gained sufficient experience over more than 10 years to evaluate esophageal cancer patients after NACRT or definitive CRT. Surgery was performed 4 weeks after the completion of NACRT. Response evaluation The response to CRT was evaluated both macroscopically and histopathologically. Endoscopic evaluation was performed in the period before NACRT and surgery. Both evaluations were performed using conventional white light and narrow band imaging (NBI). Lugol's staining and subsequent biopsy were performed before NACRT but not before surgery. Macroscopic evaluation was performed using the findings of the endoscopy and resected specimens, and histological evaluation was based on the Japanese Classification of Esophageal Cancer, 11th edition.2,11 We serially cross-sectioned the specimens at 0.5-cm intervals for entire lesion when the tumor remained, or for the lesion in which the tumor was assumed to be present before NACRT. Careful histological evaluation was performed (Fig. 1, case 22). The pathological stage of each cancer was defined according to the Union for International Cancer Control (UICC) TNM (tumor, node, metastasis) classification (7th edn.) system.12 The grading of tumor regression was based on an estimation of the percentage of viable tumor tissue in relation to the tumor bed as follows: grade 3, markedly effective (no viable residual tumor cells); grade 2, moderately effective (less than one-third residual tumor cells); grade 1, slightly effective (1b, one-third to two-thirds residual tumor cells; 1a, more than two-thirds residual tumor cells); and grade 0, ineffective (no therapeutic effect observed).2,6,12 Histopathological evaluation was performed by three pathologists (F.F., H.O., and Y.O.). In this study, we selected grade 2 and 1b cases because they might show a complete response to definitive CRT. We evaluated the presence of residual in situ lesions and residual tumor depth in these cases. In addition, we compared endoscopic or postoperative macroscopic evaluation with these clinicopathological parameters in individual patients. Fig. 1 View largeDownload slide The sectioning procedure for grade 2 disease (case no. 22). Specimens were serially cross-sectioned at 0.5-cm intervals where the entire lesion assumed to be the tumor was present before neoadjuvant chemoradiotherapy (NACRT). Fig. 1 View largeDownload slide The sectioning procedure for grade 2 disease (case no. 22). Specimens were serially cross-sectioned at 0.5-cm intervals where the entire lesion assumed to be the tumor was present before neoadjuvant chemoradiotherapy (NACRT). RESULTS Histopathological evaluation Among the 42 patients who received NACRT, five achieved a complete response by the time of surgery; namely, no residual tumor cells were detected in the esophagus or lymph nodes following extensive histopathological evaluation. In addition, two cases demonstrated a complete pathological response in the primary lesions but harbored residual carcinoma cells in the lymph nodes. Evaluation of tumor regression was performed in each case and the distribution was as follows: grade 3 (7 cases), grade 2 (16 cases), grade 1b (13 cases), and grade 1a (6 cases) (Table 1). We conducted pathological evaluation of 29 patients (grade 2 and grade 1b). Table 1 Cases characteristics: grading and pathological evaluation Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 †≧SM, invasion deeper than the submucosa (SM); ‡≧MP: invasion deeper than the muscularis propria (MP). View Large Table 1 Cases characteristics: grading and pathological evaluation Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 Case no. Age, sex Macroscopic depth prediction Pathological depth Grading of tumor regression (primary lesion) Length of intraepithelial lesion Location of tumor nests (submucosa or deeper) 1 59 M T2 T3 1a 2 64 F T4 T3 1a 3 63 M T3 T2 1a 4 54 M T3 T3 1a 5 57 M T3 T3 1a 6 68 F T3 T3 1a 7 57 M T3 T3 1b ≧5 mm 8 74 M T1b T2 1b 1 mm 9 68 M T2 T2 1b ≧5 mm 10 73 M T2 T3 1b None (Ulcer +) 11 63 M T3 T3 1b 2 mm 12 72 M T1b T1b 1b ≧5 mm 13 74 F T3 T4 1b None (Ulcer +) 14 60 M T1b T1b 1b None 15 55 M T0 T2 1b None 16 77 M T2 T3 1b 4 mm 17 55 F T4 T3 1b 4 mm 18 63 F T3 T2 1b ≧5 mm 19 59 M T3 T3 1b None 20 57 M T3 T2 2 None (Ulcer +) ≧SM† 21 64 M T2 T1b 2 None ≧SM 22 69 M T2 T3 2 None (Ulcer +) ≧MP‡ 23 60 F T2 T2 2 None (Ulcer +) ≧SM 24 71 M T2 T2 2 None 25 75 M T0 T1a 2 None 26 54 M T3 T3 2 None (Ulcer +) ≧MP 27 60 M T2 T3 2 None ≧SM 28 65 M T3 T2 2 None ≧SM 29 62 M T0 T1b 2 ≧5 mm ≧SM 30 75 M T3 T3 2 1 mm 31 72 M T3 T2 2 None 32 68 M T3 T1a 2 3 mm 33 59 M T0 T2 2 None ≧SM 34 54 M T2 T1b 2 None 35 50 M T2 T2 2 3 mm 36 75 F T2 T0 3 37 70 M T0 T0 3 38 73 M T1b T0 3 39 67 M T1b T0 3 40 62 M T0 T0 3 41 64 M T2 T0 3 42 69 M T0 T0 3 †≧SM, invasion deeper than the submucosa (SM); ‡≧MP: invasion deeper than the muscularis propria (MP). View Large Comparison between histological and macroscopic findings Among the 42 patients, the concordance rate of predictive depth between macroscopic and histopathological examination in the resected specimen was 40% (17/42). In 7 cases evaluated as T0 following macroscopic evaluation of the resected specimens, only 3 were pathologically defined as T0 based on the primary lesion. Four cases were determined to be pathologically T0, even though the presence of residual carcinoma was macroscopically suspected (Table 2). Table 2 Correlation between macroscopic and pathological findings (n = 42) Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 View Large Table 2 Correlation between macroscopic and pathological findings (n = 42) Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 Pathological findings Macroscopic findings T0 T1 T2–T4 T0 3 2 2 T1 2 2 1 T2–T4 2 3 25 View Large Intraepithelial lesion and location of tumor nests in the wall following CRT Twenty-nine cases were evaluated as grade 1b or 2. Among these 29 cases, no intraepithelial lesions were detected in 17 cases, even following detailed histopathological examination. In 12 cases harboring intraepithelial lesions, the horizontal length of the total intraepithelial lesion was less than 5 mm in 7 cases (Fig. 2, case 16). The locations of residual tumor nests in the esophageal wall of the grade 1b or 2 cases are summarized in Table 1. In nine cases, tumor nests were detected in the submucosa or muscularis propria, but were not detected in the layer above the submucosa (Fig. 3, case 22). Fig. 2 View largeDownload slide Characteristic residual pattern of mucosa (case no 16). The grading of tumor regression is 1b (A). The pathological findings indicated a residual tumor and the total intraepithelial lesion was 4 mm (B). The intraepithelial lesion is shown by the white line in A and the two arrows in B (hematoxylin and eosin staining). Fig. 2 View largeDownload slide Characteristic residual pattern of mucosa (case no 16). The grading of tumor regression is 1b (A). The pathological findings indicated a residual tumor and the total intraepithelial lesion was 4 mm (B). The intraepithelial lesion is shown by the white line in A and the two arrows in B (hematoxylin and eosin staining). Fig. 3 View largeDownload slide Macroscopic and microscopic findings of grade 2 disease (case No 22). Tumor nests were observed in only 2 areas (red points) (A). Pathological findings of residual tumor nests in muscularis propria and adventitia, respectively. The white arrow in the left upper panel in (A) and the yellow arrow in the left lower panel in (A). The panels on the right are the high-magnification versions of the panels on the left (B) (hematoxylin and eosin staining). Fig. 3 View largeDownload slide Macroscopic and microscopic findings of grade 2 disease (case No 22). Tumor nests were observed in only 2 areas (red points) (A). Pathological findings of residual tumor nests in muscularis propria and adventitia, respectively. The white arrow in the left upper panel in (A) and the yellow arrow in the left lower panel in (A). The panels on the right are the high-magnification versions of the panels on the left (B) (hematoxylin and eosin staining). DISCUSSION In this study, we evaluated 42 esophageal cancer patients who received CRT after undergoing esophageal resection. The results revealed that in the majority of grade 2 or grade 1b cases that responded to the therapy, intraepithelial lesions were not present or were only present in very small areas. In addition, carcinoma cells were not present above the submucosa in nine cases (31%). In those cases, endoscopic biopsy did not detect residual carcinoma cells, even when the procedure was performed by experienced endoscopists. These patients were considered to have a relapse of ESCC following a pathological complete response when tumors were clinically detected. Sometimes even salvage therapy, such as esophagectomy or other clinical modalities, could not improve the clinical outcome of these patients. Endoscopic biopsy cannot detect the presence of deep lesions. Therefore, patients harboring these lesions, especially those that are relatively small, have been erroneously diagnosed with a complete pathological response. This could be clinically critical for these patients, because they might miss the chance to receive further treatment, such as salvage esophagectomy. However, early clinical detection of cancer recurrence after a complete response to CRT can be very difficult. Practically, not only was the concordance rate of predictive depth between macroscopic and histopathological examination in the resected specimen low (about 40%), but in a few cases, we also made the wrong decision about whether carcinoma cells were residual or not. In addition, there is no definitive evidence regarding the appropriate timing of response evaluation and follow-up; therefore, patients diagnosed with a complete response to definitive CRT based on macroscopic endoscopic findings, as well as those of endoscopic biopsy, tend not to receive very close follow-up.13 Our study demonstrated that small cancer nests could be present under the submucosal layer, even in cases diagnosed as a clinical complete response. In those cases, cancer recurred inside the esophageal wall. However, the prognosis of patients diagnosed with a clinical complete response is considerably better than that of those diagnosed with residual cancer.6,7 Therefore, we believe that early detection of cancer recurrence is very important for additional treatment, such as salvage esophagectomy. Approximately half of patients who undergo definitive CRT develop a complete response and the esophagus is preserved; thus, definitive CRT is clearly a useful therapy.14 It is therefore essential to redesign the clinical algorithm in patients receiving CRT who are diagnosed with a clinical complete response after completion of the treatment; this will allow the detection of lesions that cannot be identified using routine endoscopic evaluation and biopsy. In addition, it is also important to clinically identify cases in which carcinoma cells disappear from the primary lesions but remain in the lymph nodes. Therefore, further examinations are necessary, such as the development of more refined endoscopic ultrasonography that could detect these lesions even when nonpathological endoscopic findings are obtained. In conclusion, pathologically negative cancer cells from ordinal biopsy are not reliable to diagnose esophageal cancer patients treated with CRT. If residual cancer is suspected based on the results of clinical modalities, such as endoscopy or PET/CT, close and repeated follow-up or total judgment is needed. This should be considered by every clinician and endoscopist involved in the clinical management of ESCC patients treated with CRT. ACKNOWLEDGMENTS We would like to thank Editage (www.editage.jp) for English language editing. Notes Specific author contributions: Fumiyoshi Fujishima and Yusuke Taniyama designed the study; Fumiyoshi Fujishima, Hiroshi Okamoto, Yohei Ozawa, Ken Ito, Hirotaka Ishida, and Takuro Konno-Kumagai collected the clinical information of the cases as needed; Fumiyoshi Fujishima, Hiroshi Okamoto, Yohei Ozawa diagnosed and evaluated the response of CRT; and Fumiyoshi Fujishima and Yusuke Taniyama mainly drafted the manuscript with some help from Yasuhiro Nakamura, Atsuko Kasajima, and Hironobu Sasano. All authors approved the final submitted version of the manuscript. Fumiyoshi Fujishima and Yusuke Taniyama contributed equally to this work. References 1 Ariga H , Nemoto K , Miyazaki S et al. Prospective comparison of surgery alone and chemoradiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus . Int J Radiat Oncol Biol Phys 2009 ; 75 : 348 – 56 . Google Scholar CrossRef Search ADS PubMed 2 Japan Esophageal Society . Japanese Classification of Esophageal Cancer, 11th Edition: part I . Esophagus 2017 ; 14 : 1 – 36 . CrossRef Search ADS PubMed 3 Kuwano H , Nishimura Y , Oyama T et al. Guidelines for diagnosis and treatment of carcinoma of the esophagus April 2012 edited by the Japan Esophageal Society . Esophagus 2015 ; 12 : 1 – 30 . Google Scholar CrossRef Search ADS PubMed 4 Nakamura R , Omori T , Takeuchi H et al. Salvage endoscopic resection as a treatment for locoregional failure or recurrence following chemoradiotherapy or radiotherapy for esophageal cancer . Oncol Lett 2016 ; 11 : 3631 – 36 . Google Scholar CrossRef Search ADS PubMed 5 Yamamoto M , Doki Y , Shiozaki H et al. Evaluation of the histologic effect of chemoradiation therapy for squamous cell carcinomas of the esophagus by assessing morphologic features of surgical specimens . Dis Esophagus 2000 ; 13 : 293 – 300 . Google Scholar CrossRef Search ADS PubMed 6 Okamoto H , Fujishima F , Nakamura Y et al. Murine double minute 2 and its association with chemoradioresistance of esophageal squamous cell carcinoma . Anticancer Res 2013 ; 33 : 1463 – 71 . Google Scholar PubMed 7 Wang S , Tachimori Y , Hokamura N et al. Prognostic analysis of salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous cell carcinoma: the importance of lymphadenectomy . J Thorac Cardiovasc Surg 2014 ; 147 : 1805 – 11 . Google Scholar CrossRef Search ADS PubMed 8 Sarkaria I S , Rizk N P , Bains M S et al. Post-treatment endoscopic biopsy is a poor predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer . Ann Surg 2009 ; 249 : 764 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Shaukat A , Mortazavi A , Demmy T et al. Should preoperative, post-chemoradiotherapy endoscopy be routine for esophageal cancer patients? Dis Esophagus 2004 ; 17 : 129 – 35 . Google Scholar CrossRef Search ADS PubMed 10 van Rossum P S , Goense L , Meziani J et al. Endoscopic biopsy and EUS for the detection of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer: a systematic review and meta-analysis . Gastrointest Endosc 2016 ; 83 : 866 – 79 . Google Scholar CrossRef Search ADS PubMed 11 Japan Esophageal Society . Japanese Classification of Esophageal Cancer, 11th Edition: part II and III . Esophagus 2017 ; 14 : 37 – 65 . CrossRef Search ADS PubMed 12 Sobin L H , Gospodarowicz M K , Wittekind C . UICC International Union Against . Cancer TNM Classification of Malignant Tumors , 7th ed . New York : Wiley-Blackwell ; 2009 . 13 Toh Y , Kitagawa Y , Kuwano H et al. A nation-wide survey of follow-up strategies for esophageal cancer patients after a curative esophagectomy or a complete response by definitive chemoradiotherapy in Japan . Esophagus 2016 ; 13 : 173 – 81 . Google Scholar CrossRef Search ADS 14 Okamoto H , Fujishima F , Kamei T et al. Murine double minute 2 predicts response of advanced esophageal squamous cell carcinoma to definitive chemoradiotherapy . BMC Cancer 2015 ; 15 : 208 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Diseases of the EsophagusOxford University Press

Published: Jul 1, 2018

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