Introduction 1 2 5 6 8 9 In the observations of the senior author (JVR), patients with solitary involved lymph nodes may achieve good outcomes, and this hypothesis was evaluated in this analysis of a large prospective database. We report herein that the cohort with a solitary node involved had cancer outcomes closer to node-negative disease than other node-positive subgroups, and suggest that this represents a distinct prognostic subgroup. Patients and Methods 10 11 A subtotal esophagectomy was performed with a sutured anastomosis either in the right thorax (two-stage) or neck (three-stage). All cases underwent a formal abdominal lymphadenectomy and mediastinal lymph node dissection up to and including the subcarinal nodes. Thoracic nodes were submitted separately to abdominal nodes. Statistical Analysis p 12 Results Patients/histology N N N 1 2 Table 1 Demographics of Nodal Subgroups Histologic Data N n N n N n N n Tumor site (%) Lower esophagus 138 (47) 39 (46) 37 (44) 57 (39) EG junction 80 (28) 35 (42) 33 (39) 75 (51) Middle esophagus 55 (19) 10 (12) 12 (14) 11 (7) Upper esophagus 16 (6) 0 2 (3) 4 (3) Morphology (%) Adenocarcinoma 140 (48) 51 (61) 57 (68) 113 (77) Squamous cell carcinoma 140 (48) 29 (35) 25 (30) 32 (22) Others 9 (4) 4 (5) 2 (1) 2 (1) Treatment (%) Multimodal therapy 129 (44) 28 (33) 24 (29) 21 (14) Surgery alone 161 (56) 56 (76) 60 (71) 125 (86) Residual tumor (%) R0: no residual tumor 250 (86) 71 (85) 64 (76) 108 (73) R1: residual tumor found 39 (13) 13 (15) 19 (23) 39 (27) Rx: unknown 1 (1) – 1 (1) – Pathological stage (%) Stage 0 53 (18) – – – Stage I 59 (20) 1 (1) – – Stage II 170 (59) 21 (25) 25 (30) 16 (11) Stage III 5 (2) 58 (29) 53 (63) 110 (76) Stage IV 1 (1) 4 (5) 6 (7) 20 (13) pT stage (%) Tx 3 (1) 0 2 (3) 1 (0.5) Tis 12 (4) 0 0 0 T0 40 (14) 1 (1) 2 (3) 2 (1) T1 56 (19) 5 (6) 4 (5) 3 (2) T2 35 (12) 16 (19) 18 (21) 12 (8) T3 138 (48) 60 (71) 54 (64) 120 (82) T4 6 (2) 2 (3) 4 (5) 8 (5) EG = esophagogastric Table 2 Histology of Nodal Subgroups Histologic Data N N N N Adeno SCC Adeno SCC Adeno SCC Adeno SCC n N n n n n n n No % No % No % No % No % No % No % No % Tumor site Lower Esophagus 64 (46) 66 (47) 19 (52) 15 (52) 23 (40) 13 (52) 39 (35) 17 (53) EG Junction 73 (52) 6 (4) 31 (10) 3 (10) 33 (58) 0 0 74 (65) 1 (3) Middle Esophagus 3 (2) 52 (37) 1 (28) 8 (28) 1 (2) 10 (40) 0 0 10 (31) Upper Esophagus 0 0 16 (11) 0 (10) 3 (10) 0 0 2 (8) 0 0 4 (13) Treatment Multimodal 80 (57) 46 (34) 23 (45) 5 (17) 20 (35) 4 (16) 19 (13) 3 (10) Surgery alone 60 (43) 93 (66) 28 (55) 24 (83) 37 (65) 21 (84) 94 (87) 28 (90) Path stage Stage 0 29 (21) 18 (13) 0 0 0 0 0 0 0 0 0 0 0 0 Stage 1 42 (30) 15 (10) 1 (2) 0 0 0 0 0 0 0 0 0 0 Stage 2 66 (47) 102 (73) 15 (29) 4 (14) 19 (33) 5 (20) 15 (13) 1 (3) Stage 3 2 (1) 4 (3) 32 (63) 24 (83) 35 (61) 17 (68) 82 (73) 27 (84) Stage 4 0 0 1 (1) 3 (6) 1 (3) 3 (6) 3 (12) 16 914) 3 (10) Unknown 1 (1) 0 0 0 0 0 0 0 0 0 0 0 0 1 (3) pT stage Tx 2 (1) 1 (1) 0 0 0 0 0 0 2 (8) 0 0 1 (3) Tis 9 (6) 0 0 0 0 0 0 2 (4) 0 0 0 0 0 0 T0 19 (14) 17 (12) 1 (2) 0 0 3 (5) 0 0 2 (2) 0 0 T1 39 (29) 15 (11) 4 (8) 0 0 14 (24) 0 0 3 (3) 0 0 T2 16 (11) 19 (14) 12 (23) 3 (10) 36 (63) 4 (16) 11 (10) 1 (3) T3 53 (38) 84 (60) 33 (65) 26 (90) 2 (4) 17 (68) 91 (80) 28 (88) T4 2 (1) 4 (2) 1 (2) 0 0 0 0 2 (8) 6 (5) 2 (6) Adeno = adenocarcinoma, SCC = small cell carcinoma, EG = esophagogastric p N N N p N p Survival N 3 p p N N N p p Table 3 Univariate and Multivariate Analysis: All Patients Variables No. of Patients Median Survival (moths) p a HR a p b HR 95% CI Treatment Surgery only 401 13 0.077 1  – – – Multimodal 203 19  0.84 0.69–1.02    Tumor site Upper esophagus 25 16 0.371 1  – – – Middle esophagus 87 14 0.946 0.98 0.58–1.66    Lower esophagus 268 14 0.658 1.16 0.69–1.81    EG junction 224 14 0.624 1.13 0.69–1.84    Depth of invasion T0 57 55 <0.001 1  0.652 1  T1 68 26 0.537 1.16 0.73–1.83 0.472 0.71 0.21–2.3 T2 81 26 0.419 1.20 0.77–1.85 0.573 1.11 0.31–3.94 T3 373 11 <0.001 2.28 1.60–3.26 0.871 1.40 0.79–2.41 T4 19 7 <0.001 4.34 2.46–7.68 0.649 2.59 1.42–4.08 No. of nodes 0 289 26 <0.001 1  <0.001 1 0.63–1.87 1 84 16 0.038 1.36 1.02–1.82 0.774 1.08 0.83–2.43 2–3 84 11 <0.001 1.91 1.45–2.52 0.202 1.42 1.07–3.18 >3 147 8 <0.001 2.61 2.08–3.29 0.027 1.84  Histology Squamous 361 14 0.916 1     Adenocarcinoma 224 13 0.596 1.05 0.87–1.28 – – – Other 19 26 0.483 0.80 0.44–1.48    Stage 0 53 55 <0.001 1  0.118 1  I 63 55 0.747 0.92 0.56–1.51 0.576 0.68 0.18–2.59 II 230 20 0.037 1.49 1.02–2.17 0.508 1.55 0.42–4.69 III 225 10 <0.001 2.71 1.86–3.95 0.527 1.68 0.34–5.58 IV 31 6 <0.001 6.16 3.72–10.2 0.182 3.14 1.14–7.76 Residual tumor R0 492 17 <0.001 1  0.052 1  R1 110 8  1.70 1.37–2.12  1.25 0.99–1.58 a χ 2 b HR = hazard ratio, CI = 95% confidence intervals, EG = esophagogastric 1 Figure 1 Overall survival by number of nodes positive.  3 p 4 5 p p p Table 4 Univariate Analysis: Node-positive Alone Variables No. of Patients Median Survival (moths) p a HR 95% CI Treatment Surgery only 241 11 0.234 1 0.63–1.11 Multimodal 74 11  0.84  Tumor site Upper esophagus 9 18 0.650 1  Middle esophagus 32 10 0.556 1.31 0.54–3.18 Lower esophagus 130 10 0.183 1.75 0.77–3.98 OG junction 144 12 0.350 1.48 0.65–3.36 Depth of invasion T0 5 11 0.001 1  T1 12 8 0.917 1.06 0.33–3.41 T2 46 24 0.176 1.12 0.43–1.78 T3 235 11 0.757 1.43 0.74–2.14 T4 14 5 0.157 2.23 0.74–6.78 Histology Squamous 86 11 0.638 1  Adenocarcinoma 221 11 0.638 1.07 0.81–1.40 Other 8 3 0.848 1.07 0.49–2.35 Stage 1–II 63 19 <0.001 1  III–IV 251 10  2.01 1.43–2.83 Residual tumor R0 259 12 0.035 1  R1 61 9  1.33 1.02–1.73 No. of nodes 1 84 17 <0.001 1  2–3 84 13 0.021 1.67 1.06–2.29 >3 147 9 <0.001 2.53 1.50–3.62 a χ 2 HR = hazard ratio, CI = 95% confidence intervals Table 5 Mutivariate Analysis: Node-positive Only Variables p a HR 95% CI Depth of invasion T0  1  T1 0.544 0.82 0.31–1.75 T2 0.679 1.23 0.74–1.81 T3 0.313 1.49 0.99–2.21 T4 0.202 1.83 1.39–3.24 Stage I–II 0.010 1  III–IV  1.59 0.82–3.06 No. of nodes 1  1  2–3 0.049 1.56 1.21–2.35 >3 0.007 2.06 1.51–2.82 Residual tumor R0 0.283 1  R1  1.22 0.80–1.79 a HR = hazard ratio, CI = 95% confidence intervals Discussion 13 3 14 15 16 18 19 19 The clinical implication of this finding is not clear at this time, but it should, at minimum, encourage a more optimistic view of patients who have a solitary lymph node identified after adequate lymphadenectomy, as approximately 35% of patients with this pathologic stage may be cured. In the future, it is possible that advances in endoscopic US staging, fluorodeoxyglucose PET, and sentinel node assessment may improve pre- and intraoperative assessment of nodal involvement, defining node-negative, solitary involved node and micrometastatic-involved subgroups, and selective lymphadenectomy and minimally invasive approaches may be evaluated in these situations. This demands prospective evaluation, but it may be noteworthy that all involved nodes in the solitary involved node cohort were close to the primary site and may possibly have been identified as sentinel nodes. In conclusion, this study shows that in a large cohort of patients, lymph node status and the number of lymph nodes positive at the time of surgical resection is directly linked to survival. Extensive nodal involvement is confirmed as carrying a dismal prognosis, but greater optimism is justified where a solitary involved lymph gland defines the pN stage after an adequate lymphadenectomy.