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Prognostic Factors in T1 and T2 Squamous Cell Carcinoma of the Thoracic Esophagus

Prognostic Factors in T1 and T2 Squamous Cell Carcinoma of the Thoracic Esophagus BackgroundPrognostic indicators in patients with T2 tumor have not been fully understood.ObjectiveTo clarify the clinicopathologic characteristics and long-term results of T1 and T2 squamous cell carcinomas of the thoracic esophagus.DesignConsecutive case series.SettingDepartment of surgery in a university hospital.PatientsOf 234 patients with primary squamous cell carcinoma of the thoracic esophagus, 142 patients underwent esophagectomy with curative intent: 97 patients had pT1 and pT2 tumors.InterventionsInvestigated were clinicopathologic characteristics of 65 of 97 patients with pT1 and pT2 tumors; excluded were 7 patients who died of postoperative complications and another 25 patients who died of causes other than esophageal cancer.Main Outcome MeasuresClinicopathologic characteristics and long-term results.ResultsPathologic tumor stages were pT1 N0 in 23 patients, pT1 N(+) in 7 patients, pT2 N0 in 15 patients, and pT2 N(+) in 20 patients. Fifty patients are alive and free of cancer and 15 patients died of tumor recurrence (1 patient with pT1 N0 tumor, 1 patient with pT1 N[+][+] tumor, 1 patient with pT2 N0 tumor, and 12 patients with pT2 N[+] tumor). The sites of metastatic nodes in 6 survivors with pT1 N(+) tumor were a solitary perigastric node in 4 patients, a solitary mediastinal node in 1 patient, and 2 mediastinal nodes in 1 patient. The 5-year survival rates of patients with pT1 N0, pT1 N(+), and pT2 N0 tumors all exceeded 85%, and the rate of those with pT2 N(+) tumor was 33.9% (pT2 N[+] vs others: pT1 N0, pT1 N[+], and pT2 N0; P=.003). The factors affecting survival rate by univariate analysis were Borrmann classification (0, 1 vs 2, 3, 4), tumor size (<4.0 vs ≥4.0 cm), combined T, N factor (pT2 N[+] vs others), time of operation (≤420 vs >420 minutes), estimated blood loss (<1000 vs ≥1000 mL), and lymph vessel invasion (marked vs not marked). Stage pT2 N(+) tumor became a single independent prognostic factor for survival as determined by multivariate analysis (pT2 N[+] vs others; P=.008).ConclusionsStage pT1 N(+) tumors with a few diseased nodes and pT2 N0 tumors are considered to be a group with an excellent prognosis, similar to pT1 N0 tumors. Patients with pT2 N(+) diseases had worse prognoses and thus should have meticulous lymph node dissection and extensive adjuvant therapy.ESOPHAGEAL carcinoma is one of the most malignant tumors, with a dismal prognosis. Among several clinicopathologic factors affecting the outcomes of patients with esophageal carcinoma, the depth of penetration is the crucial factor determining the prognosis.Patients with superficial (T1) esophageal carcinoma have a significantly favorable clinical course compared with those with advanced cancers. The outcome for patients with T1 cancer is excellent, with a 5-year disease-specific survival rate exceeding 80%.Conversely, the prognosis of patients with locally advanced (T3 and T4) tumor is far from satisfactory.Prognostic indicators, however, in patients with T2 tumor have not been fully understood.The operative approach for esophageal cancer varies from conventional transthoracic esophagectomy chiefly for palliationto wide local excision with extensive lymphadenectomy with curative intentto limited excision without thoracotomy.The confusing factors are that adenocarcinomas of the gastric cardia invading the esophagus and those arising from the Barrett esophagus are reviewed in the literature, but their biologic behavior may be different from that of epidermoid cancer. Therefore, such adenocarcinomas of the esophagus were excluded from this study.To clarify the clinicopathologic characteristics of early-stage squamous cell carcinoma of the thoracic esophagus, data from patients with T1 and T2 tumors were retrospectively investigated. Because these tumors must be evaluated in a series of resected specimens pathologically proven, this study included patients who had undergone surgical intervention.PATIENTS AND METHODSBetween December 1979 and November 1997, 234 patients with primary squamous cell carcinoma of the thoracic esophagus were admitted to the Second Department of Surgery, Shimane Medical University, Shimane, Japan. Of these, 142 patients (60.7%) underwent esophagectomy with curative intent: 97 patients (68.3%) had pT1 and pT2 esophageal tumors and the remaining 45 patients (31.7%) had pT3 and pT4 tumors. Of these 97 patients with pT1 and pT2 tumors, excluded were 7 patients (7.2%) who died of postoperative complications during the hospital stay and another 25 patients (25.8%) who died of causes other than esophageal cancer, ie, pneumonia or respiratory failure (5 patients), second cancer (5 patients [hepatocellular cancer in 2 patients and gastric tube cancer, sigmoid colon cancer, and pancreas cancer each in 1 patient]), severe emaciation (4 patients), aging (3 patients), cardiac problems (2 patients), cerebrovascular attack (2 patients), and choking accident, gastric tube ulcer perforation, liver failure, and unknown sudden death at home (each in 1 patient). Therefore, 65 patients were enrolled in this analysis.Most patients underwent a right transthoracic subtotal esophagectomy and dissection of the cervical (bilateral supraclavicular regions), mediastinal (periesophagus and around the trachea), and abdominal (perigastric lesion and around the celiac axis) lymph nodes. Reconstruction was usually carried out with a gastric tube through the retrosternal route, and esophagogastrostomy was done in the neck under the cervical and abdominal incisions.When the tumor invaded the deeper submucosal layer, 1 or 2 cycles of adjuvant radiochemotherapy was routinely administered. Patients with T2 tumor received 2 cycles of the same schedule of chemotherapy with radiotherapy. One cycle of chemotherapy consisted of bolus administration of cisplatin (50 mg/m2per day) on the 1st and 15th days and continuous intravenous infusion of fluorouracil (300 mg/m2) for 28 days. One cycle of radiotherapy consisted of 1.8 Gy daily directed to the tumor bed. The total dosage was 30.6 Gy.Clinicopathologic characteristics of these 65 patients were investigated based on the TNM classification of malignant tumors.The outcomes of patients were examined, and those who clearly died of recurrence were regarded as tumor-related deaths. In calculating the 10-year survival rate, those who were alive more than 10 years were counted as being alive at 10 years.Survival rates were estimated by the Kaplan-Meier method,and statistical analysis was carried out by the log-rank test to test for equality of the survival curves. In multivariate analysis, independent prognostic factors were determined using a Cox proportional hazards model(StatView J4.5, Abacus Concepts Inc, Berkeley, Calif). The level of significance was P<.05.RESULTSPathologic tumor stages were pT1 N0 in 23 patients, pT1 N(+) in 7 patients, pT2 N0 in 15 patients, and pT2 N(+) in 20 patients. Fifty patients are alive and free of cancer at the time of this analysis. Fifteen patients died because of recurrence: 1 patient with pT1 N0 tumor, 1 patient with pT1 N(+) tumor, 1 patient with pT2 N0 tumor, and 12 patients with pT2 N(+) tumor. The overall 1-, 3-, 5-, and 10-year survival rates of all 65 patients were 91.3%, 77.4%, 72.1%, and 68.1%, respectively.SITES OF LYMPH NODE METASTASIS IN pT1 N(+) AND pT2 N(+) TUMORSIn 7 patients with pT1 N(+) tumor, the sites of diseased nodes were a solitary perigastric node in 4 patients, a solitary mediastinal node in 1 patient, 2 mediastinal nodes in 1 patient, and multiple cervical and mediastinal nodes in 1 patient who died of recurrence.In 20 patients with pT2 N(+) tumor, the sites of metastatic nodes were a solitary perigastric node in 4 patients, mediastinal nodes in 4 patients, mediastinal and perigastric nodes in 3 patients, coeliac nodes (M1a) with mediastinal nodes in 4 patients, and cervical (M1a) and mediastinal nodes in 5 patients.ADJUVANT TREATMENTForty-five patients received adjuvant treatment. Of 23 patients with pT1 N0 tumor, 17 patients did not receive any adjuvant treatment and 6 patients received adjuvant radiochemotherapy. Of 7 patients with pT1 N(+) tumor, 6 patients received radiochemotherapy and 1 patient refused any adjuvant treatment. Of 35 patients with pT2 tumor, 25 patients received adjuvant radiochemotherapy and 8 patients with shallow muscle layer invasion received chemotherapy alone. The remaining 2 patients refused any adjuvant treatment.CUMULATIVE SURVIVAL RATES OF PATIENTS WITH pT1 AND pT2 TUMORS ACCORDING TO LYMPH NODE METASTASISThe 5-year survival rates of patients with pT1 N0, pT1 N(+), and pT2 N0 tumors were satisfactory, all exceeding 85% (Figure 1and Figure 2). Conversely, 12 of 20 patients with pT2 N(+) tumor died of recurrence, and the 5-year survival rate was 33.9% (pT2 N[+] vs others: pT1 N0, pT1 N[+], and pT2 N0; P=.003) (Figure 3).Figure 1. Cumulative survival curves of patients with pT1 esophageal cancer according to lymph node metastasis. The 3- and 5-year survival rates were 100% for those without lymph node metastasis (n=23) and 85.7% for those with lymph node metastasis (n=7) (P=.57, log-rank test).Figure 2. Cumulative survival curves of patients with pT2 esophageal cancer according to lymph node metastasis. The 3- and 5-year survival rates were 90% for those without lymph node metastasis (n=15) and 47.5% and 33.9%, respectively, for those with lymph node metastasis (n=20) (P=.003, log-rank test).Figure 3. Cumulative survival curves of patients with pT1 and pT2 esophageal cancers according to combined T, N factor. The 3- and 5-year survival rates were 93.8% for those with pT1 N0, pT1 N(+), and pT2 N0 diseases (n=45) and 47.5% and 33.9%, respectively, for those with pT2 N(+) disease (n=20) (P<.001, log-rank test).CLINICOPATHOLOGIC FACTORS AFFECTING SURVIVAL RATETable 1shows the clinicopathologic variables affecting the cumulative survival rates by univariate analysis. The variables affecting survival rate were Borrmann classification (0,1 vs 2,3,4), tumor size (≤4.0 vs >4.0 cm), combined T, N factor (pT2 N[+] vs others), time of operation (≤420 vs >420 minutes), estimated blood loss (<1000 vs ≥1000 mL), and lymph vessel invasion (marked vs not marked). Sex, histological differentiation, and vessel invasion did not affect the survival rate.Table 1. Clinicopathologic Features and Prognosis of Patients With T1 and T2 Esophageal CancerSurvival Rate, %&ast;VariablePatients, No. (%)1 y3 y5 y10 yPSexFemale4 (6)10010050. . ..97Male61 (94)93767469Age, y≤6537 (57)91736464.43>6528 (43)96848473Tumor locationNonupper59 (91)92817671.12Upper6 (9)75505050Borrmann classification0, 142 (65)97878781.0082, 3, 423 (35)82645050Size of tumor, cm<4.031 (48)100909081.03≥4.034 (52)84685959Combined T, N factorpT1, pT2 NO45 (69)97949487.001pT2 N(+)20 (31)74483434Time of operation, min≤42053 (82)94838080.01>42012 (18)75504242Blood loss, mL<100049 (75)95858176.03≥100016 (25)74605050Histological differentiationWell24 (37)81705252.21Nonwell41 (63)97827575Lymph vessel invasionNot marked60 (92)91827773.006Marked5 (8)7525. . .. . .Blood vessel invasionNot marked60 (92)92797470.31Marked5 (8)606060. . .RadiotherapyYes34 (52)85706262.09No31 (48)96909072&ast;Ellipses indicate no survivors during this time.PROGNOSTIC SIGNIFICANCE EVALUATED BY MULTIVARIATE ANALYSISAmong those 6 significant variables verified by univariate analysis, stage pT2 N(+) tumor was a single independent prognostic factor for survival as determined by multivariate analysis (pT2 N[+] vs others; P=.008) (Table 2). Therefore, pT1 N(+) and pT2 N0 diseases are considered to be a group with an excellent prognosis, similar to pT1 N0 tumor.Table 2. Multivariate Analysis of Prognostic Factors for Survival Using a Cox Proportional Hazards ModelVariables&ast;CoefficientPHazard Ratio95% CI†pT2 N(+)1.90.0086.651.64-26.92Time of operation1.50.164.500.55-37.02Size of tumor1.07.112.910.78-10.90Borrmann type0.88.132.400.76-7.55Lymph vessel invasion0.79.282.200.53-9.10Blood loss−0.71.520.490.06-4.27&ast;Variables are categorized as in Table 1.†CI indicates confidence interval.COMMENTDepth of invasion is a major denominator deciding the prognosis of esophageal cancer. The prognosis of patients with T1 tumoris generally good, but the therapeutic result is far from satisfactory for locally advanced (T3 and T4) tumors.Although patients with T2 tumor are generally considered to have a favorable prognosis, recurrence of the disease occurs in a certain number of patients. Therefore, it is necessary to identify the high-risk group and to design an appropriate therapy for better survival.The incidence of T1 and T2 esophageal cancer so far reported varies from 13.1% to 52.2%,and the 5-year survival rate of these patients has been reported to be 22.5% to 88.2%.These data are comparable to the 68.3% incidence of T1 and T2 tumors and 72.1% 5-year survival rate in the present study.Unlike patients with early gastric carcinoma, the prognosis of patients with esophageal carcinoma is considered to be dismal once the regional lymph nodes are involved.However, several European series, including that reported by Hoelscher et al,found no significant difference in survival between the node-positive and node-negative group in T1 tumor and concluded that nodal status was not an independent prognostic factor by multivariate analysis. Similarly, we demonstrated that there was no significant difference in survival between the pT1 N0 and pT1 N(+) groups, and the 5-year survival rates were excellent, exceeding 85% in both groups. This indicates that a certain number of patients with diseased regional lymph nodes might have excellent survival when the primary tumor is pT1. Also, this survival advantage in patients with pT1 N(+) tumor could be associated with the extent and site of involvement of the regional lymph nodes. In these series, only 1 patient with pT1 N(+) tumor died of recurrence and had extensive lymph node involvement at multiple anatomical fields, and all other surviving patients had only a few (<2) metastatic nodes either in the mediastinum or in the perigastric region. Nishimaki et alshowed that survival rates of patients with metastases to a single anatomical field were better than those with metastases to 2 fields, similar to another report.Moreover, the number of patients who received adjuvant treatment was high (6 of 7 patients) compared with another study.Therefore, although the number of patients is small in this study, those with a few metastatic nodes confined to a single anatomical region who undergo proper adjuvant therapy are considered to be a group with an excellent prognosis, similar to those with pT1 N0 diseases.By TNM classification,pT1 N0 tumor is classified as stage I and pT2 N0 tumor as stage IIa. Stage pT2 N0 tumors, however, yielded an excellent survival rate that was similar to that of pT1 N0 diseases in the present study. Killinger et alcompared the survival results in stage II esophageal carcinoma and revealed that survival was not different between T1 N0 and T2 N0 disease (both 50% of 5-year survival rate; P=.83). They concluded that the distinction between these subgroups was not warranted. Similarly, Skinner et algrouped submucosal (T1) and T2 tumors in 1 group because without any lymph node metastasis, patients with T1 and T2 tumors have similar survival. There are several possible explanations for such contradictory results. First, most reports included patients with esophageal carcinoma of different pathologic backgrounds, for example, squamous cell carcinoma and adenocarcinomas, making the interpretation difficult.Second, we considered only disease-specific deaths to evaluate the prognosis, but most othersevaluated the prognosis as overall survival. Last, subtle variations among different institutions, surgeons, or patient characteristics could be another factor. Because our survival data are better than those previously reported, we assume that pT2 N0 disease should be categorized as a group with an excellent prognosis, similar to pT1 N0 tumors.Our results indicate that pT1 N(+) tumors with a few metastatic nodes confined to a single anatomical region and pT2 N0 tumors are considered to be a group with an excellent prognosis, similar to pT1 N0 diseases. However, once the tumor was metastasized to the lymph nodes, the prognosis of pT2 tumor became worse. To improve the prognosis of patients with pT2 N(+) tumors, meticulous lymph node dissection and extensive adjuvant therapy might be important.RGiuliHSGarnierDiagnostic, therapeutic, and prognostic features of cancers of the esophagus: results of the international prospective study conducted by the OESO group (790 patients).Surgery.1986;99:614-622.FHEllisSPGibbEWatkinsEsophagogastrectomy: a safe, widely applicable, and expeditious form of palliation for patients with carcinoma of the esophagus and cardia.Ann Surg.1983;198:531-540.DBSkinnerEn bloc resection for neoplasms of the esophagus and cardia.J Thorac Cardiovasc Surg.1983;85:59-71.MTachibanaHYoshlmuraSKinugasaClinicopathological features of superficial squamous cell carcinoma of the esophagus.Am J Surg.1997;174:49-53.KSugimachiSOhnoHMatsudaMMoriHMatsuokaHKuwanoClinicopathologic study of early stage esophageal carcinoma.Surgery.1989;105:706-710.APeracchiaARuolLBonavinaEarly squamous cell carcinoma of the esophagus: diagnosis and management.Dig Surg.1989;6:109-113.SAbeMTachibanaTShimokawaMShiraishiTNakamuraSurgical treatment of advanced carcinoma of the esophagus.Surg Gynecol Obstet.1989;168:115-120.JMDalyLHKarnellHRMenckNational cancer data base report on esophageal carcinoma.Cancer.1996;78:1820-1828.TIizukaKIsonoTKakegawaHWatanabeParameters linked to ten-year survival in Japan of resected esophageal carcinoma.Chest.1989;96:1005-1011.FHEllisGJHeatleyMJKrasnaWAWilliamsonKBaloghEsophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria.J Thorac Cardiovasc Surg.1997;113:836-848.MBOrringerTranshiatal esophagectomy without thoracotomy for carcinoma of the thoracic esophagus.Ann Surg.1984;200:282-288.UICC staffTNM Classification of Malignant Tumours.5th ed. New York, NY: Wiley-Liss Inc; 1997.ELKaplanPMeierNonparametric estimation for incomplete observations.J Am Stat Assoc.1958;53:457-481.DRCoxRegression models and life tables.J R Stat Soc Ser B.1972;34:187-220.MFokSYKLawJWongOperable esophageal carcinoma: current results from Hong Kong.World J Surg.1994;18:355-360.HKatoYTachimoriHWatanabeHIgakiYNakanishiAOchlaiRecurrent esophageal carcinoma after esophagectomy with three-field lymph node dissection.J Surg Oncol.1996;61:267-272.TJungingerPDutkowskiSelective approach to the treatment of oesophageal cancer.Br J Surg.1996;83:1473-1477.HIdeTNakamuraKHayashiEsophageal squamous cell carcinoma: pathology and prognosis.World J Surg.1994;18:321-330.DBSkinnerMKFergusonASorianoAGLittleVMStaszakSelection of operation for esophageal cancer based on staging.Ann Surg.1986;204:391-401.WAKillingerTWRiceDJAdelsteinStage II esophageal carcinoma: the significance of T and N.J Thorac Cardiovasc Surg.1996;111:935-940.HYoshinakaHShimazuTFukumotoMBabaSuperficial esophageal carcinoma: a clinicopathological review of 59 cases.Am J Gastroenterol.1991;86:1413-1418.HKatoYTachimoriHWatanabeSuperficial esophageal carcinoma: surgical treatment and the results.Cancer.1990;66:2319-2323.KSugimachiMIkebeKKitamuraYTohHMatsudaHKuwanoLong-term results of esophagectomy for early esophageal carcinoma.Hepatogastroenterology.1993;40:203-206.AHHoelscherEBollschweilerPMSchneiderJRSiewertPrognosis of early esophageal cancer: comparison between adeno- and squamous cell carcinoma.Cancer.1995;76:178-186.TNishimakiTSuzukiSSuzukiSKuwabaraKHatakeyamaOutcomes of extended radical esophagectomy for thoracic esophageal cancer.J Am Coll Surg.1998;186:306-312.KYanoTOkamuraYYoshidaTEzakiKYasumotoThe extent and number of metastatic lymph nodes limit the efficacy of lymphadenectomy in patients with oesophageal carcinoma.Surg Oncol.1994;3:187-192.Reprints: Mitsuo Tachibana, MD, Second Department of Surgery, Shimane Medical University, Enya-cho 89-1, Izumo 693-8501, Shimane, Japan (e-mail: nigeka33@shimane-med.ac.jp). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Surgery American Medical Association

Prognostic Factors in T1 and T2 Squamous Cell Carcinoma of the Thoracic Esophagus

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Publisher
American Medical Association
Copyright
Copyright 1999 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6254
eISSN
2168-6262
DOI
10.1001/archsurg.134.1.50
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Abstract

BackgroundPrognostic indicators in patients with T2 tumor have not been fully understood.ObjectiveTo clarify the clinicopathologic characteristics and long-term results of T1 and T2 squamous cell carcinomas of the thoracic esophagus.DesignConsecutive case series.SettingDepartment of surgery in a university hospital.PatientsOf 234 patients with primary squamous cell carcinoma of the thoracic esophagus, 142 patients underwent esophagectomy with curative intent: 97 patients had pT1 and pT2 tumors.InterventionsInvestigated were clinicopathologic characteristics of 65 of 97 patients with pT1 and pT2 tumors; excluded were 7 patients who died of postoperative complications and another 25 patients who died of causes other than esophageal cancer.Main Outcome MeasuresClinicopathologic characteristics and long-term results.ResultsPathologic tumor stages were pT1 N0 in 23 patients, pT1 N(+) in 7 patients, pT2 N0 in 15 patients, and pT2 N(+) in 20 patients. Fifty patients are alive and free of cancer and 15 patients died of tumor recurrence (1 patient with pT1 N0 tumor, 1 patient with pT1 N[+][+] tumor, 1 patient with pT2 N0 tumor, and 12 patients with pT2 N[+] tumor). The sites of metastatic nodes in 6 survivors with pT1 N(+) tumor were a solitary perigastric node in 4 patients, a solitary mediastinal node in 1 patient, and 2 mediastinal nodes in 1 patient. The 5-year survival rates of patients with pT1 N0, pT1 N(+), and pT2 N0 tumors all exceeded 85%, and the rate of those with pT2 N(+) tumor was 33.9% (pT2 N[+] vs others: pT1 N0, pT1 N[+], and pT2 N0; P=.003). The factors affecting survival rate by univariate analysis were Borrmann classification (0, 1 vs 2, 3, 4), tumor size (<4.0 vs ≥4.0 cm), combined T, N factor (pT2 N[+] vs others), time of operation (≤420 vs >420 minutes), estimated blood loss (<1000 vs ≥1000 mL), and lymph vessel invasion (marked vs not marked). Stage pT2 N(+) tumor became a single independent prognostic factor for survival as determined by multivariate analysis (pT2 N[+] vs others; P=.008).ConclusionsStage pT1 N(+) tumors with a few diseased nodes and pT2 N0 tumors are considered to be a group with an excellent prognosis, similar to pT1 N0 tumors. Patients with pT2 N(+) diseases had worse prognoses and thus should have meticulous lymph node dissection and extensive adjuvant therapy.ESOPHAGEAL carcinoma is one of the most malignant tumors, with a dismal prognosis. Among several clinicopathologic factors affecting the outcomes of patients with esophageal carcinoma, the depth of penetration is the crucial factor determining the prognosis.Patients with superficial (T1) esophageal carcinoma have a significantly favorable clinical course compared with those with advanced cancers. The outcome for patients with T1 cancer is excellent, with a 5-year disease-specific survival rate exceeding 80%.Conversely, the prognosis of patients with locally advanced (T3 and T4) tumor is far from satisfactory.Prognostic indicators, however, in patients with T2 tumor have not been fully understood.The operative approach for esophageal cancer varies from conventional transthoracic esophagectomy chiefly for palliationto wide local excision with extensive lymphadenectomy with curative intentto limited excision without thoracotomy.The confusing factors are that adenocarcinomas of the gastric cardia invading the esophagus and those arising from the Barrett esophagus are reviewed in the literature, but their biologic behavior may be different from that of epidermoid cancer. Therefore, such adenocarcinomas of the esophagus were excluded from this study.To clarify the clinicopathologic characteristics of early-stage squamous cell carcinoma of the thoracic esophagus, data from patients with T1 and T2 tumors were retrospectively investigated. Because these tumors must be evaluated in a series of resected specimens pathologically proven, this study included patients who had undergone surgical intervention.PATIENTS AND METHODSBetween December 1979 and November 1997, 234 patients with primary squamous cell carcinoma of the thoracic esophagus were admitted to the Second Department of Surgery, Shimane Medical University, Shimane, Japan. Of these, 142 patients (60.7%) underwent esophagectomy with curative intent: 97 patients (68.3%) had pT1 and pT2 esophageal tumors and the remaining 45 patients (31.7%) had pT3 and pT4 tumors. Of these 97 patients with pT1 and pT2 tumors, excluded were 7 patients (7.2%) who died of postoperative complications during the hospital stay and another 25 patients (25.8%) who died of causes other than esophageal cancer, ie, pneumonia or respiratory failure (5 patients), second cancer (5 patients [hepatocellular cancer in 2 patients and gastric tube cancer, sigmoid colon cancer, and pancreas cancer each in 1 patient]), severe emaciation (4 patients), aging (3 patients), cardiac problems (2 patients), cerebrovascular attack (2 patients), and choking accident, gastric tube ulcer perforation, liver failure, and unknown sudden death at home (each in 1 patient). Therefore, 65 patients were enrolled in this analysis.Most patients underwent a right transthoracic subtotal esophagectomy and dissection of the cervical (bilateral supraclavicular regions), mediastinal (periesophagus and around the trachea), and abdominal (perigastric lesion and around the celiac axis) lymph nodes. Reconstruction was usually carried out with a gastric tube through the retrosternal route, and esophagogastrostomy was done in the neck under the cervical and abdominal incisions.When the tumor invaded the deeper submucosal layer, 1 or 2 cycles of adjuvant radiochemotherapy was routinely administered. Patients with T2 tumor received 2 cycles of the same schedule of chemotherapy with radiotherapy. One cycle of chemotherapy consisted of bolus administration of cisplatin (50 mg/m2per day) on the 1st and 15th days and continuous intravenous infusion of fluorouracil (300 mg/m2) for 28 days. One cycle of radiotherapy consisted of 1.8 Gy daily directed to the tumor bed. The total dosage was 30.6 Gy.Clinicopathologic characteristics of these 65 patients were investigated based on the TNM classification of malignant tumors.The outcomes of patients were examined, and those who clearly died of recurrence were regarded as tumor-related deaths. In calculating the 10-year survival rate, those who were alive more than 10 years were counted as being alive at 10 years.Survival rates were estimated by the Kaplan-Meier method,and statistical analysis was carried out by the log-rank test to test for equality of the survival curves. In multivariate analysis, independent prognostic factors were determined using a Cox proportional hazards model(StatView J4.5, Abacus Concepts Inc, Berkeley, Calif). The level of significance was P<.05.RESULTSPathologic tumor stages were pT1 N0 in 23 patients, pT1 N(+) in 7 patients, pT2 N0 in 15 patients, and pT2 N(+) in 20 patients. Fifty patients are alive and free of cancer at the time of this analysis. Fifteen patients died because of recurrence: 1 patient with pT1 N0 tumor, 1 patient with pT1 N(+) tumor, 1 patient with pT2 N0 tumor, and 12 patients with pT2 N(+) tumor. The overall 1-, 3-, 5-, and 10-year survival rates of all 65 patients were 91.3%, 77.4%, 72.1%, and 68.1%, respectively.SITES OF LYMPH NODE METASTASIS IN pT1 N(+) AND pT2 N(+) TUMORSIn 7 patients with pT1 N(+) tumor, the sites of diseased nodes were a solitary perigastric node in 4 patients, a solitary mediastinal node in 1 patient, 2 mediastinal nodes in 1 patient, and multiple cervical and mediastinal nodes in 1 patient who died of recurrence.In 20 patients with pT2 N(+) tumor, the sites of metastatic nodes were a solitary perigastric node in 4 patients, mediastinal nodes in 4 patients, mediastinal and perigastric nodes in 3 patients, coeliac nodes (M1a) with mediastinal nodes in 4 patients, and cervical (M1a) and mediastinal nodes in 5 patients.ADJUVANT TREATMENTForty-five patients received adjuvant treatment. Of 23 patients with pT1 N0 tumor, 17 patients did not receive any adjuvant treatment and 6 patients received adjuvant radiochemotherapy. Of 7 patients with pT1 N(+) tumor, 6 patients received radiochemotherapy and 1 patient refused any adjuvant treatment. Of 35 patients with pT2 tumor, 25 patients received adjuvant radiochemotherapy and 8 patients with shallow muscle layer invasion received chemotherapy alone. The remaining 2 patients refused any adjuvant treatment.CUMULATIVE SURVIVAL RATES OF PATIENTS WITH pT1 AND pT2 TUMORS ACCORDING TO LYMPH NODE METASTASISThe 5-year survival rates of patients with pT1 N0, pT1 N(+), and pT2 N0 tumors were satisfactory, all exceeding 85% (Figure 1and Figure 2). Conversely, 12 of 20 patients with pT2 N(+) tumor died of recurrence, and the 5-year survival rate was 33.9% (pT2 N[+] vs others: pT1 N0, pT1 N[+], and pT2 N0; P=.003) (Figure 3).Figure 1. Cumulative survival curves of patients with pT1 esophageal cancer according to lymph node metastasis. The 3- and 5-year survival rates were 100% for those without lymph node metastasis (n=23) and 85.7% for those with lymph node metastasis (n=7) (P=.57, log-rank test).Figure 2. Cumulative survival curves of patients with pT2 esophageal cancer according to lymph node metastasis. The 3- and 5-year survival rates were 90% for those without lymph node metastasis (n=15) and 47.5% and 33.9%, respectively, for those with lymph node metastasis (n=20) (P=.003, log-rank test).Figure 3. Cumulative survival curves of patients with pT1 and pT2 esophageal cancers according to combined T, N factor. The 3- and 5-year survival rates were 93.8% for those with pT1 N0, pT1 N(+), and pT2 N0 diseases (n=45) and 47.5% and 33.9%, respectively, for those with pT2 N(+) disease (n=20) (P<.001, log-rank test).CLINICOPATHOLOGIC FACTORS AFFECTING SURVIVAL RATETable 1shows the clinicopathologic variables affecting the cumulative survival rates by univariate analysis. The variables affecting survival rate were Borrmann classification (0,1 vs 2,3,4), tumor size (≤4.0 vs >4.0 cm), combined T, N factor (pT2 N[+] vs others), time of operation (≤420 vs >420 minutes), estimated blood loss (<1000 vs ≥1000 mL), and lymph vessel invasion (marked vs not marked). Sex, histological differentiation, and vessel invasion did not affect the survival rate.Table 1. Clinicopathologic Features and Prognosis of Patients With T1 and T2 Esophageal CancerSurvival Rate, %&ast;VariablePatients, No. (%)1 y3 y5 y10 yPSexFemale4 (6)10010050. . ..97Male61 (94)93767469Age, y≤6537 (57)91736464.43>6528 (43)96848473Tumor locationNonupper59 (91)92817671.12Upper6 (9)75505050Borrmann classification0, 142 (65)97878781.0082, 3, 423 (35)82645050Size of tumor, cm<4.031 (48)100909081.03≥4.034 (52)84685959Combined T, N factorpT1, pT2 NO45 (69)97949487.001pT2 N(+)20 (31)74483434Time of operation, min≤42053 (82)94838080.01>42012 (18)75504242Blood loss, mL<100049 (75)95858176.03≥100016 (25)74605050Histological differentiationWell24 (37)81705252.21Nonwell41 (63)97827575Lymph vessel invasionNot marked60 (92)91827773.006Marked5 (8)7525. . .. . .Blood vessel invasionNot marked60 (92)92797470.31Marked5 (8)606060. . .RadiotherapyYes34 (52)85706262.09No31 (48)96909072&ast;Ellipses indicate no survivors during this time.PROGNOSTIC SIGNIFICANCE EVALUATED BY MULTIVARIATE ANALYSISAmong those 6 significant variables verified by univariate analysis, stage pT2 N(+) tumor was a single independent prognostic factor for survival as determined by multivariate analysis (pT2 N[+] vs others; P=.008) (Table 2). Therefore, pT1 N(+) and pT2 N0 diseases are considered to be a group with an excellent prognosis, similar to pT1 N0 tumor.Table 2. Multivariate Analysis of Prognostic Factors for Survival Using a Cox Proportional Hazards ModelVariables&ast;CoefficientPHazard Ratio95% CI†pT2 N(+)1.90.0086.651.64-26.92Time of operation1.50.164.500.55-37.02Size of tumor1.07.112.910.78-10.90Borrmann type0.88.132.400.76-7.55Lymph vessel invasion0.79.282.200.53-9.10Blood loss−0.71.520.490.06-4.27&ast;Variables are categorized as in Table 1.†CI indicates confidence interval.COMMENTDepth of invasion is a major denominator deciding the prognosis of esophageal cancer. The prognosis of patients with T1 tumoris generally good, but the therapeutic result is far from satisfactory for locally advanced (T3 and T4) tumors.Although patients with T2 tumor are generally considered to have a favorable prognosis, recurrence of the disease occurs in a certain number of patients. Therefore, it is necessary to identify the high-risk group and to design an appropriate therapy for better survival.The incidence of T1 and T2 esophageal cancer so far reported varies from 13.1% to 52.2%,and the 5-year survival rate of these patients has been reported to be 22.5% to 88.2%.These data are comparable to the 68.3% incidence of T1 and T2 tumors and 72.1% 5-year survival rate in the present study.Unlike patients with early gastric carcinoma, the prognosis of patients with esophageal carcinoma is considered to be dismal once the regional lymph nodes are involved.However, several European series, including that reported by Hoelscher et al,found no significant difference in survival between the node-positive and node-negative group in T1 tumor and concluded that nodal status was not an independent prognostic factor by multivariate analysis. Similarly, we demonstrated that there was no significant difference in survival between the pT1 N0 and pT1 N(+) groups, and the 5-year survival rates were excellent, exceeding 85% in both groups. This indicates that a certain number of patients with diseased regional lymph nodes might have excellent survival when the primary tumor is pT1. Also, this survival advantage in patients with pT1 N(+) tumor could be associated with the extent and site of involvement of the regional lymph nodes. In these series, only 1 patient with pT1 N(+) tumor died of recurrence and had extensive lymph node involvement at multiple anatomical fields, and all other surviving patients had only a few (<2) metastatic nodes either in the mediastinum or in the perigastric region. Nishimaki et alshowed that survival rates of patients with metastases to a single anatomical field were better than those with metastases to 2 fields, similar to another report.Moreover, the number of patients who received adjuvant treatment was high (6 of 7 patients) compared with another study.Therefore, although the number of patients is small in this study, those with a few metastatic nodes confined to a single anatomical region who undergo proper adjuvant therapy are considered to be a group with an excellent prognosis, similar to those with pT1 N0 diseases.By TNM classification,pT1 N0 tumor is classified as stage I and pT2 N0 tumor as stage IIa. Stage pT2 N0 tumors, however, yielded an excellent survival rate that was similar to that of pT1 N0 diseases in the present study. Killinger et alcompared the survival results in stage II esophageal carcinoma and revealed that survival was not different between T1 N0 and T2 N0 disease (both 50% of 5-year survival rate; P=.83). They concluded that the distinction between these subgroups was not warranted. Similarly, Skinner et algrouped submucosal (T1) and T2 tumors in 1 group because without any lymph node metastasis, patients with T1 and T2 tumors have similar survival. There are several possible explanations for such contradictory results. First, most reports included patients with esophageal carcinoma of different pathologic backgrounds, for example, squamous cell carcinoma and adenocarcinomas, making the interpretation difficult.Second, we considered only disease-specific deaths to evaluate the prognosis, but most othersevaluated the prognosis as overall survival. Last, subtle variations among different institutions, surgeons, or patient characteristics could be another factor. 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Journal

JAMA SurgeryAmerican Medical Association

Published: Jan 1, 1999

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