- Email: [email protected]
Clinicopathologic Features of Submucosal Esophageal Squamous Cell Carcinoma
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Clinicopathologic Features of Submucosal Esophageal Squamous Cell Carcinoma Manabu Emi, MD, PhD, Jun Hihara, MD, PhD, Yoichi Hamai, MD, PhD, Takaoki Furukawa, MD, PhD, Yuta Ibuki, MD, and Morihito Okada, MD, PhD Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Background. The prognoses of submucosal esophageal squamous cell carcinoma patients vary. Patients with favorable prognoses may receive less invasive or nonsurgical interventions, whereas patients with poor prognoses or advanced esophageal cancer may require aggressive treatments. We sought to identify prognostic factors for patients with submucosal esophageal squamous cell carcinoma, focusing on lymph node metastasis and recurrence. Methods. We included 137 submucosal esophageal squamous cell carcinoma patients who had undergone transthoracic esophagectomy with systematic extended lymph node dissection. Submucosal tumors were classified as SM1, SM2, and SM3 according to the depth of invasion. Prognostic factors were determined by univariable and multivariable analyses. Results. Lymph node metastasis was observed in 18.8%, 30.5%, and 50.0% of SM1, SM2, and SM3 cases, respectively. The overall 5-year recurrence rate was 21.9%; the rates for SM1, SM2, and SM3 tumors were
9.4%, 18.6%, and 34.8%, respectively. The SM1 tumors all recurred locoregionally; distant metastasis occurred in SM2 and SM3 cases. The 5-year overall survival rates were 83%, 77%, and 59% for SM1, SM2, and SM3 cases, respectively. On univariable analysis, lymph node metastasis, depth of submucosal invasion (SM3 versus SM1/2), and tumor location (upper thoracic versus mid/ lower thoracic) were poor prognostic factors for overall survival. Multivariable Cox regression analyses identified depth of submucosal invasion (hazard ratio 2.51, 95% confidence interval: 1.37 to 4.61) and tumor location (hazard ratio 2.43, 95% confidence interval: 1.18 to 4.63) as preoperative prognostic factors. Conclusions. Tumor location (upper thoracic) and infiltration (SM3) are the worse prognostic factors of submucosal esophageal squamous cell carcinoma, but lymph node metastasis is not a predictor of poorer prognosis.
T
disease-free survival of T1bN1 patients in particular is poorer [5]. Another study concluded that limited lymphadenectomy is not acceptable because of the relatively high frequency of skipped metastatic lymph nodes [10]. Therefore, further studies on the frequency and pattern of lymph node metastasis are required to determine the indication of less invasive surgical approaches such as transhiatal esophagostomy. Nonsurgical approaches include endoscopic therapy and chemoradiotherapy. Endoscopic therapy appears to be effective in limiting tumor spreading to the lamina propria mucosa, but is not suitable for patients with submucosal carcinoma because of the high incidence of lymph node metastasis [6, 11, 12]. The efficacy of concurrent chemoradiotherapy against superficial esophageal cancer has recently been demonstrated, and chemoradiotherapy combined with endoscopic therapy may become an alternative therapeutic approach to esophagectomy for clinical T1N0M0 esophageal cancers [13, 14]. However, the irradiation field remains unclear; hence, analysis of the pattern of lymph node metastasis and recurrence in patients with submucosal esophageal squamous cell carcinoma (SESCC) is required to improve its delineation. Conversely, some superficial esophageal cancer has worse prognostic aspects such as advanced esophageal
he number of diagnosed superficial esophageal carcinoma cases, defined as esophageal carcinoma limited to the submucosal layer, has increased owing to recent progress in endoscopic screening with the Lugol dye method as well as narrow band imaging [1, 2]. Many studies indicate that submucosal esophageal cancer is highly associated with lymph node metastasis [3–6], and surgical resection has been the prominent curative treatment in patients with this disease [7]. Although the prognosis of patients with superficial esophageal cancer treated with surgery is more favorable, the surgery itself can be associated with a decreased quality of life [8]. Therefore, less invasive surgical approaches such as laparoscopic transhiatal esophagostomy are increasingly being used [9]. Prognosis after transhiatal esophagostomy is reportedly similar to that after transthoracic esophagectomy with extended lymphadenectomy; however, Accepted for publication June 12, 2017. Presented at the Thirteenth World Congress of the International Society for Diseases of the Esophagus, Venice, Italy, Oct 15–17, 2012. Address correspondence to Dr Emi, Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
(Ann Thorac Surg 2017;104:1858–64) Ó 2017 by The Society of Thoracic Surgeons
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cancer. Angiolymphatic invasion, lymph node metastasis, histologic grade, and SM3 invasion have been reported to be independent prognostic factors for advanced disease; however, these risk factors have not been properly validated [4, 6, 15]. Some studies have indicated that preoperative or postoperative chemotherapy for stage IIB esophageal squamous cell carcinoma, which includes T1N1 cases, is effective [16, 17]. If worse prognostic subgroups such as advanced esophageal cancer can be detected, these subgroups may be candidates for neoadjuvant or adjuvant therapy. In the present study, we examined surgical outcomes and patterns of lymph node metastasis and recurrence in patients with SESCC treated with esophagectomy at a single institution. We considered the optimal extent of lymph node dissection and adequate irradiation field according to the tumor location and invasion depth among patients with superficial esophageal cancer. Furthermore, we aimed to identify poor prognostic factors in superficial esophageal cancer patients who may benefit from adjuvant therapy.
Patients and Methods Patient Population The Institutional Review Board of Hiroshima University Hospital, Hiroshima, Japan, approved this retrospective study. The retrospective study included 137 consecutive patients with early esophageal squamous cell carcinoma that invaded only as far as the submucosa (T1b) who underwent esophagectomy at our institution between January 1990 and December 2011. Our inclusion criteria for participation in the study were as follows: (1) SESCC with submucosal invasion was diagnosed after postoperative histopathology examination; (2) the patient underwent transthoracic esophagectomy with radical lymphadenectomy; and (3) the patient did not receive neoadjuvant chemotherapy or chemoradiotherapy. Upper gastrointestinal barium swallow, upper gastrointestinal endoscopy, and computed tomography of the neck, chest, and upper abdomen were performed for all cases as preoperative examinations. Postoperative adjuvant chemotherapy, which consisted of two courses of either intravenous docetaxel (50 mg/m2, day 1) plus 5fluorouracil (700 mg/m2 days 1 through 5), or cisplatin (80 mg/m2, day 1) plus 5-fluorouracil (800 mg/m2 days 1 through 5), was administered to patients with pathologically confirmed metastasis to the lymph nodes. Since 2005, 7 patients received the former, and another 7 received the latter. The eligibility criteria were as follows: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and sufficient organ function.
Surgery and Pathology Examination Patients in whom the primary tumor was located in the upper or mid-thoracic esophagus underwent transthoracic esophagectomy with two-field or three-field lymphadenectomy (McKeown esophagectomy, except for 2 cases in which Ivor-Lewis esophagectomy was
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performed). Patients whose primary tumors were located in the lower thoracic esophagus underwent transthoracic esophagectomy with two-field lymphadenectomy. Reconstruction was usually performed through a gastric tube by the posterior mediastinal or retrosternal route. All resection specimens were assessed by a senior pathologist, and histopathologic classification was performed according to the seventh edition of the Union for International Cancer Control TNM classification of malignant tumors [18]. The invasion depths of submucosal (SM) lesions were divided into equal thirds: SM1 (shallow invasion), SM2 (invasion into the middle third), and SM3 (deep invasion) [7]. In 3 patients with multicentric cancers, the tumor with the deepest depth of infiltration or largest diameter was considered the main tumor. All resected lymph nodes were identified according to their location, counted, and assessed separately. The locations of the initial lymph nodes were categorized into five compartments in accordance with the Japanese Classification of Esophageal Cancer [19]: cervix, upper thoracic, mid thoracic, lower thoracic, and abdomen. Upper thoracic lymph nodes included recurrent nerve nodes and paraesophageal nodes beyond the carina, mid thoracic lymph nodes included paratracheal nodes and mid thoracic esophageal nodes, and lower thoracic lymph nodes included lower thoracic esophageal nodes.
Follow-Up and Statistical Analysis Patients received follow-up, including with computed tomography every 3 months for the first year, every 4 months the next year, every 6 months in the subsequent 3 years, and once a year thereafter. The median follow-up time for these patients was 71 months. Endoscopic examination was performed annually. Any signs of suspicious lesions, including by cytology, histology, radiology (ie, computed tomography, magnetic response imaging, positron emission tomography, bone scan, and ultrasonography), or clinical signs were regarded as a recurrent disease. Regional lymph node recurrence was defined as nonlocal recurrence within the surgically dissected area. All data were reviewed in April 2016. The overall survival was calculated from the date of surgery until the date of last follow-up or death using the Kaplan-Meier method, and any statistical differences were then examined by univariable analysis by using the log rank test. Four patients who died of complications after esophagectomy were included in the survival analysis. Survival rates were calculated using the Kaplan-Meier method and analyzed by using the log rank test. Independent predictive factors for survival were performed with the Cox regression method model using the backward option. All statistical analyses were performed using the SPSS software, version 10.5 (SPSS, Chicago, IL). Differences were considered to be significant at an alpha risk of 5%.
Results There were 119 men and 18 women with a mean age of 64 years (range, 47 to 81); their clinicopathologic characteristics are shown in Table 1. All patients had squamous cell
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Table 1. Clinicopathologic Characteristics of 137 Patients With Submucosal Esophageal Cancer Characteristics
Values 64 8
Age at surgery, years Sex Male Female Tumor location Upper thoracic Mid thoracic Lower thoracic Histology SCC Tumor differentiation Well Moderate Poor Unknown Depth of submucosal invasion SM1 SM2 SM3 Pathologic N category pN0 pN1, 1–2 LN pN2, 3–6 LN pN3, >6 LN Pathologic M category pM0 pM1 Resection category R0
119 (86.9) 18 (13.1) 26 83 28 137 (100) 17 61 43 16 32 59 46 90 41 6 0 133 4 137 (100)
Values are mean SD, n (%), or n. LN ¼ lymph node; submucosal.
SCC ¼ squamous cell carcinoma;
SM ¼
carcinoma. A complete macroscopic and microscopic resection of the primary tumor (R0 resection) was achieved in all patients, of whom 41 underwent three-field lymphadenectomy and 90 underwent two-field lymphadenectomy. There were 4 patients with pM1 stage because of M1 lymph node metastasis. The median number of resected lymph nodes was 35 (range, 15–78). The rate of lymph node metastasis increased stepwise according to the depth of wall penetration (Table 2). Of 46 patients with SM3 invasion, 23 (50.0%) had lymph node metastasis. Table 2. Depth of Tumor Infiltration and Rate of Lymph Node Metastasis in Submucosal Esophageal Cancer Tumor Depth
n
pNþ
p Value
SM1 SM2 SM3
32 59 46
6 (18.8) 18 (30.5) 23 (50.0)
. 0.3196 0.0082
Values are n (%). pN ¼ pathologic node;
SM ¼ submucosal.
Table 3 shows the distribution of metastatic lymph nodes as related to the locations of esophageal tumors. With upper thoracic esophageal cancers, metastatic lymph nodes were almost always detected in the cervical or upper thoracic regions. With mid esophageal cancers, there was a wide distribution of cervical, thoracic, and abdominal lymph nodes. With lower esophageal cancers, cervical or upper thoracic lymph node involvement was not detected. The mean follow-up period for all patients was 71 months; 30 patients (21.9%) had recurrence after esophagectomy. The patterns of recurrence according to the depth of invasion are shown in Table 4. Recurrence occurred in only 3 patients (9.4%) with SM1 carcinoma, and all recurrences were in the regional lymph nodes (ie, lymph nodes in areas inside the operative field) whereas recurrence was observed in 11 patients (18.6%) with SM2 carcinoma, of which 8 were limited to regional lymph nodes. Distant metastasis occurred when the tumors had infiltrated into deeper layers beyond SM1 and occurred most frequently with SM3 carcinomas. Local recurrence developed in none of the patients with SM carcinoma in our study. Among all patients, except those who died of esophageal cancer, there were 26 (21.8%) with metachronous cancer. The sites of the other primary malignancies were the head and neck in 8 patients, lung in 7 patients, stomach in 3 patients, and other areas in 10 patients. The 5-year and 10-year cause-specific survival rates were 96.2% and 96.2% for SM1 carcinoma, 92.2% and 89.9% for SM2 carcinoma, and 68.6% and 68.6% for SM3 carcinoma, respectively (Fig 1A). The 5-year and 10-year overall survival rates were 83.3% and 73.7% for SM1 carcinoma, 83.5% and 73.7% for SM2 carcinoma, and 58.1% and 54.9% for SM3 carcinoma, respectively (Fig 1B). Comparisons of overall survival among patients with SM1 or SM2 carcinoma showed no significant difference (p ¼ 0.565); therefore, the prognoses of patients with SM1/ SM2 versus SM3 was analyzed. On univariable analysis, tumor size (p ¼ 0.3076), tumor differentiation (p ¼ 0.9286), and angiolymphatic invasion (p ¼ 0.7156) had no effect on survival. Besides depth of submucosal invasion (p ¼ 0.0030), overall survival was significantly influenced by pathologic lymph node status (p ¼ 0.0467) and tumor location (p ¼ 0.0038). On multivariable survival analysis using the Cox proportional hazards model, significant correlations were noted between overall survival and each of depth of submucosal invasion (p ¼ 0.003) and tumor location (p ¼ 0.007). However, there was no significant correlation between overall survival and pathologic lymph node status (Table 5).
Comment The main finding of this study is that a depth of invasion deeper than SM1 signified higher rates of recurrence and distant metastasis. However, the prognoses of SM2 patients (5-year survival 83.3%) were similar to those of SM1 patients (5-year survival 83.3%), whereas the prognoses of
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Table 3. Primary Tumor Location and Lymph Node Metastasis in Patients With Submucosal Esophageal Cancer Lymph Node Metastasis Tumor Location Upper thoracic (n ¼ 7) Mid thoracic (n ¼ 28) Lower thoracic (n ¼ 12)
Cervical
Upper Thoracic
Mid Thoracic
Lower Thoracic
Abdominal
3 (43) 1 (4) 0 (0)
5 (71) 8 (29) 0 (0)
0 (0) 5 (18) 1 (8)
0 (0) 6 (21) 3 (25)
1 (14) 15 (54) 10 (83)
Values are n (%).
SM3 patients (5-year survival 58.1%) were significantly worse than for patients with more superficial submucosal invasion, and were closer to those of patients with locally advanced disease. Only 3 patients with SM1 (9.4%) had recurrence, whereas 11 SM2 patients (18.6%) had recurrence. However, the 5-year survival rate for patients with SM2 was identical to that of patients with SM1, possibly because of death due to other causes such as primary malignancy and the relatively good prognosis in patients with SM2. Of 8 patients with SM2 who had regional lymph node recurrence, 3 are still alive after having received additional chemoradiation therapy or surgery (7 to 11 years after regional lymph node recurrence); such episodes may suggest comparatively good prognoses in patients with SM2. Conversely, the poor prognosis of SM3 esophageal cancer can be explained by anatomic and oncologic features of the submucosal esophageal cancer. The esophageal lymphatic anatomy in the mucosa and submucosa was recently found to be nonhomogeneous by using D2-40 immunohistochemical staining. In the submucosa, lymphatics appear to be concentrated in the deep submucosa and have direct connections to more central lymphatic channels [20, 21]. Therefore, increasing the depth of submucosal invasion leads to greater risks of regional or distant lymph node metastases; that is considered to be one of the reasons why deep submucosal invasion is associated with poor survival. In terms of oncologic features, various features such as the expression of metalloproteinases, as well as proteases such as trypsin, are involved in neovascularization and tumorinduced proteolysis. These enzymes have been found to be expressed at higher levels in tumors that invade Table 4. Depth of Tumor Infiltration and Recurrence Patterns in Submucosal Esophageal Cancer Tumor Depth SM1 (n ¼ 32) SM2 (n ¼ 59)
n (%)
Recurrence Patterns (n)
3 (9.4)
Lymph node (3) (Regional lymph node: 3) Lymph node (10) (Regional lymph node: 8) Distant (1) Lymph node (8) (Regional lymph node: 7) Distant (10) .
11 (18.6)
SM3 (n ¼ 46)
16 (34.8)
Total (n ¼ 137)
30 (21.9)
SM ¼ submucosal.
deeper into the submucosa [22–24]; their expression may be associated with the increased malignant potential of SM3 esophageal squamous cell carcinomas. What constitutes an adequate extent of lymphadenectomy during surgery for submucosal esophageal cancer is controversial. Some studies recommended extended three-field lymphadenectomy for all patients with early tumors, irrespective of tumor location and histologic type, because lymph node metastasis will be found relatively frequently in the upper mediastinum or cervical region [25, 26]. Conversely, dissection of recurrent nerve and cervical nodes may impair swallowing functions, which can reduce the postoperative quality of life [8]. In the present study, an analysis of the distribution of lymph node metastases according to the tumor location showed that, in patients with lower esophageal carcinoma, neck and upper thorax lymph node metastasis is extremely rare. In terms of an adequate extent of lymph node dissection, cervical lymph node dissection may be avoidable for patients with lower-third superficial esophageal cancers. A second novel finding in this study is that patients with upper thoracic superficial esophageal carcinoma have significantly lower survival expectancies than do patients with mid or lower thoracic superficial esophageal carcinoma. Prognosis has not been reported to be influenced by tumor location; in particular, no studies to evaluate the prognosis of superficial esophageal carcinoma by the primary site have been performed to the best of our knowledge [15, 27, 28]. Of 26 patients with upper thoracic esophageal carcinoma, cervicothoracic lymph node metastasis occurred in 7 (27%), as compared with 8 of 111 patients with mid or lower thoracic esophageal carcinoma (7%) who had cervicothoracic lymph node metastasis. Complete dissection of the cervicothoracic nodes around the upper thoracic esophagus is technically difficult, which may be the reason for the poor prognosis of upper thoracic superficial esophageal cancer patients. In general, lymph node metastasis is widely characterized as being associated with worse survival outcomes in patients with submucosal esophageal cancer [6, 15, 29, 30]. Although lymph node metastasis was previously identified as a prognostic factor on univariable and multivariable analysis, it was not of prognostic value for the SESCC patients in the present study. In a recent study of submucosal esophageal cancer, no difference in survival was observed between patients with positive lymph node metastasis and those without [31]. The investigators in that study considered that the extent of lymph node
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Fig 1. (a) Cause-specific survival rates as a function of tumor depth in 137 patients who underwent primary surgical resection for submucosal (SM) thoracic esophageal squamous cell carcinoma. (b) Overall survival rates as a function of tumor depth in 137 patients who underwent primary surgical resection for submucosal thoracic esophageal squamous cell carcinoma. The SM3 carcinoma (broken lines) had a poorer outcome than SM1 (dotted lines) or SM2 (solid lines) carcinoma (p ¼ 0.003).
dissection by esophagectomy was different from that in most previous studies that included limited lymphadenectomies such as transhiatal esophagectomy. In the present study, the 5-year overall survival rates were 83.6% for SM1/2 with positive lymph node metastasis and 82.7% for SM1/2 with negative lymph node
metastasis, and there was no significant difference in prognosis between these two groups. Conversely, the 5-year overall survival rate of SM3 was 73.7% for nodenegative cases, but 41.7% for node-positive cases, indicating a significantly poorer prognosis for nonpositive cases (p ¼ 0.0311). As we have mentioned, SM1/2 and
Table 5. Univariable and Multivariable Analysis of Prognostic Factors for Overall Survival Multivariable Analysis Variable Age, years <65 65 Tumor size, cm <5 5 Tumor differentiation Well or moderate Poor Angiolymphatic invasion Present Not present pN status pN >1 pN0 Depth of SM invasion SM3 SM1/2 Tumor location Upper thoracic Mid, lower thoracic CI ¼ confidence interval;
n
5-Year OS
p Value
74 63
78.1% 70.4%
0.5603
95 42
74.3% 73.3%
0.3076
78 43
74.7% 70.0%
0.9286
86 45
71.8% 81.0%
0.7156
46 85
62.7% 81.1%
46 91 26 111 HR ¼ hazard ratio;
HR
95% CI
p Value
0.0467
1.567
0.831–2.958
0.165
58.1% 83.4%
0.0030
2.513
1.373–4.606
0.003
56.0% 79.2%
0.0038
2.433
1.184–4.628
0.007
OS ¼ overall survival;
pN ¼ pathologic node;
SM ¼ submucosal.
SM3 esophageal cancer have different anatomic and oncologic features. We suggest that these differences may explain why many SM1/2 carcinomas remain local diseases, even though the cases are positive for lymph node metastasis. However, when the depth of invasion has progressed to SM3, positivity for lymph node metastasis indicates that the esophageal carcinoma is progressing to systemic disease. We therefore inferred that prognosis would be significantly poorer for SM3 with lymph node metastasis. Based on these considerations, we view lymph node metastasis as a prognostic factor in SM3 carcinoma, but not in SM carcinoma as a whole. Moreover, given that patients with lymph node metastasis have been undergoing postoperative adjuvant chemotherapy since 2005, and that long-term follow-up visits help detect new malignancies, may dampen the influence of lymph node metastasis on survival. A limitation of this study is that it was a singleinstitution investigation that represented a highly selected population (although it spanned more than 20 years). As it was a surgical series, patients with submucosal cancers that were not medically operable were not represented. In conclusion, we found that upper thoracic or SM3 esophageal squamous cell carcinomas have a poor prognosis. A recent randomized study suggested that neoadjuvant chemotherapy with cisplatin and 5fluorouracil followed by surgery improved overall survival of patients with clinical stage II or III esophageal squamous cell carcinoma, including T1b [6]. Although determining the depth of submucosal invasion is difficult, neoadjuvant chemotherapy may improve the prognosis of SESCC patients suspected of having deeply infiltrative submucosal lesions or tumors located in the upper thoracic esophagus. Further prospective clinical trials are required to assess the efficacy of neoadjuvant therapy for these patients.
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8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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The Thoracic Surgery Foundation: For 29 Years, Turning Today’s Research Into Tomorrow’s Patient Care Our patients don’t follow the details of our research. They don’t discuss unexpected breakthroughs or technical setbacks. They are not always aware of how changes in health care policies impact research funding and lab time. Nonetheless, the advances we make in cardiothoracic surgery touch each and every one of them. New surgical techniques and potent new drugs improve patient health and extend patient lives. The Thoracic Surgery Foundation (TSF) is a pivotal force for growth and vitality in cardiothoracic surgery, especially for research and academic career development. TSF was first established in 1988 as a 501(c)(3) not-for-profit charitable foundation with support from the four major thoracic surgery organizations—the American Association for Thoracic Surgery, The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and the Western Thoracic Surgical Association. On October 1, 2014, TSF became the official charitable arm of The Society of Thoracic Surgeons. The foundation represents thoracic surgery in the United States and its research and educational initiatives support the broad spectrum of thoracic surgery. The mission of TSF is to foster the development of surgeon scientists in cardiothoracic surgery; increasing knowledge and innovation to benefit patient care.
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Clinicopathologic Features of Submucosal Esophageal Squamous Cell Carcinoma Manabu Emi, MD, PhD, Jun Hihara, MD, PhD, Yoichi Hamai, MD, PhD, Takaoki Furukawa, MD, PhD, Yuta Ibuki, MD, and Morihito Okada, MD, PhD Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Background. The prognoses of submucosal esophageal squamous cell carcinoma patients vary. Patients with favorable prognoses may receive less invasive or nonsurgical interventions, whereas patients with poor prognoses or advanced esophageal cancer may require aggressive treatments. We sought to identify prognostic factors for patients with submucosal esophageal squamous cell carcinoma, focusing on lymph node metastasis and recurrence. Methods. We included 137 submucosal esophageal squamous cell carcinoma patients who had undergone transthoracic esophagectomy with systematic extended lymph node dissection. Submucosal tumors were classified as SM1, SM2, and SM3 according to the depth of invasion. Prognostic factors were determined by univariable and multivariable analyses. Results. Lymph node metastasis was observed in 18.8%, 30.5%, and 50.0% of SM1, SM2, and SM3 cases, respectively. The overall 5-year recurrence rate was 21.9%; the rates for SM1, SM2, and SM3 tumors were
9.4%, 18.6%, and 34.8%, respectively. The SM1 tumors all recurred locoregionally; distant metastasis occurred in SM2 and SM3 cases. The 5-year overall survival rates were 83%, 77%, and 59% for SM1, SM2, and SM3 cases, respectively. On univariable analysis, lymph node metastasis, depth of submucosal invasion (SM3 versus SM1/2), and tumor location (upper thoracic versus mid/ lower thoracic) were poor prognostic factors for overall survival. Multivariable Cox regression analyses identified depth of submucosal invasion (hazard ratio 2.51, 95% confidence interval: 1.37 to 4.61) and tumor location (hazard ratio 2.43, 95% confidence interval: 1.18 to 4.63) as preoperative prognostic factors. Conclusions. Tumor location (upper thoracic) and infiltration (SM3) are the worse prognostic factors of submucosal esophageal squamous cell carcinoma, but lymph node metastasis is not a predictor of poorer prognosis.
T
disease-free survival of T1bN1 patients in particular is poorer [5]. Another study concluded that limited lymphadenectomy is not acceptable because of the relatively high frequency of skipped metastatic lymph nodes [10]. Therefore, further studies on the frequency and pattern of lymph node metastasis are required to determine the indication of less invasive surgical approaches such as transhiatal esophagostomy. Nonsurgical approaches include endoscopic therapy and chemoradiotherapy. Endoscopic therapy appears to be effective in limiting tumor spreading to the lamina propria mucosa, but is not suitable for patients with submucosal carcinoma because of the high incidence of lymph node metastasis [6, 11, 12]. The efficacy of concurrent chemoradiotherapy against superficial esophageal cancer has recently been demonstrated, and chemoradiotherapy combined with endoscopic therapy may become an alternative therapeutic approach to esophagectomy for clinical T1N0M0 esophageal cancers [13, 14]. However, the irradiation field remains unclear; hence, analysis of the pattern of lymph node metastasis and recurrence in patients with submucosal esophageal squamous cell carcinoma (SESCC) is required to improve its delineation. Conversely, some superficial esophageal cancer has worse prognostic aspects such as advanced esophageal
he number of diagnosed superficial esophageal carcinoma cases, defined as esophageal carcinoma limited to the submucosal layer, has increased owing to recent progress in endoscopic screening with the Lugol dye method as well as narrow band imaging [1, 2]. Many studies indicate that submucosal esophageal cancer is highly associated with lymph node metastasis [3–6], and surgical resection has been the prominent curative treatment in patients with this disease [7]. Although the prognosis of patients with superficial esophageal cancer treated with surgery is more favorable, the surgery itself can be associated with a decreased quality of life [8]. Therefore, less invasive surgical approaches such as laparoscopic transhiatal esophagostomy are increasingly being used [9]. Prognosis after transhiatal esophagostomy is reportedly similar to that after transthoracic esophagectomy with extended lymphadenectomy; however, Accepted for publication June 12, 2017. Presented at the Thirteenth World Congress of the International Society for Diseases of the Esophagus, Venice, Italy, Oct 15–17, 2012. Address correspondence to Dr Emi, Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan; email: [email protected].
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cancer. Angiolymphatic invasion, lymph node metastasis, histologic grade, and SM3 invasion have been reported to be independent prognostic factors for advanced disease; however, these risk factors have not been properly validated [4, 6, 15]. Some studies have indicated that preoperative or postoperative chemotherapy for stage IIB esophageal squamous cell carcinoma, which includes T1N1 cases, is effective [16, 17]. If worse prognostic subgroups such as advanced esophageal cancer can be detected, these subgroups may be candidates for neoadjuvant or adjuvant therapy. In the present study, we examined surgical outcomes and patterns of lymph node metastasis and recurrence in patients with SESCC treated with esophagectomy at a single institution. We considered the optimal extent of lymph node dissection and adequate irradiation field according to the tumor location and invasion depth among patients with superficial esophageal cancer. Furthermore, we aimed to identify poor prognostic factors in superficial esophageal cancer patients who may benefit from adjuvant therapy.
Patients and Methods Patient Population The Institutional Review Board of Hiroshima University Hospital, Hiroshima, Japan, approved this retrospective study. The retrospective study included 137 consecutive patients with early esophageal squamous cell carcinoma that invaded only as far as the submucosa (T1b) who underwent esophagectomy at our institution between January 1990 and December 2011. Our inclusion criteria for participation in the study were as follows: (1) SESCC with submucosal invasion was diagnosed after postoperative histopathology examination; (2) the patient underwent transthoracic esophagectomy with radical lymphadenectomy; and (3) the patient did not receive neoadjuvant chemotherapy or chemoradiotherapy. Upper gastrointestinal barium swallow, upper gastrointestinal endoscopy, and computed tomography of the neck, chest, and upper abdomen were performed for all cases as preoperative examinations. Postoperative adjuvant chemotherapy, which consisted of two courses of either intravenous docetaxel (50 mg/m2, day 1) plus 5fluorouracil (700 mg/m2 days 1 through 5), or cisplatin (80 mg/m2, day 1) plus 5-fluorouracil (800 mg/m2 days 1 through 5), was administered to patients with pathologically confirmed metastasis to the lymph nodes. Since 2005, 7 patients received the former, and another 7 received the latter. The eligibility criteria were as follows: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and sufficient organ function.
Surgery and Pathology Examination Patients in whom the primary tumor was located in the upper or mid-thoracic esophagus underwent transthoracic esophagectomy with two-field or three-field lymphadenectomy (McKeown esophagectomy, except for 2 cases in which Ivor-Lewis esophagectomy was
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performed). Patients whose primary tumors were located in the lower thoracic esophagus underwent transthoracic esophagectomy with two-field lymphadenectomy. Reconstruction was usually performed through a gastric tube by the posterior mediastinal or retrosternal route. All resection specimens were assessed by a senior pathologist, and histopathologic classification was performed according to the seventh edition of the Union for International Cancer Control TNM classification of malignant tumors [18]. The invasion depths of submucosal (SM) lesions were divided into equal thirds: SM1 (shallow invasion), SM2 (invasion into the middle third), and SM3 (deep invasion) [7]. In 3 patients with multicentric cancers, the tumor with the deepest depth of infiltration or largest diameter was considered the main tumor. All resected lymph nodes were identified according to their location, counted, and assessed separately. The locations of the initial lymph nodes were categorized into five compartments in accordance with the Japanese Classification of Esophageal Cancer [19]: cervix, upper thoracic, mid thoracic, lower thoracic, and abdomen. Upper thoracic lymph nodes included recurrent nerve nodes and paraesophageal nodes beyond the carina, mid thoracic lymph nodes included paratracheal nodes and mid thoracic esophageal nodes, and lower thoracic lymph nodes included lower thoracic esophageal nodes.
Follow-Up and Statistical Analysis Patients received follow-up, including with computed tomography every 3 months for the first year, every 4 months the next year, every 6 months in the subsequent 3 years, and once a year thereafter. The median follow-up time for these patients was 71 months. Endoscopic examination was performed annually. Any signs of suspicious lesions, including by cytology, histology, radiology (ie, computed tomography, magnetic response imaging, positron emission tomography, bone scan, and ultrasonography), or clinical signs were regarded as a recurrent disease. Regional lymph node recurrence was defined as nonlocal recurrence within the surgically dissected area. All data were reviewed in April 2016. The overall survival was calculated from the date of surgery until the date of last follow-up or death using the Kaplan-Meier method, and any statistical differences were then examined by univariable analysis by using the log rank test. Four patients who died of complications after esophagectomy were included in the survival analysis. Survival rates were calculated using the Kaplan-Meier method and analyzed by using the log rank test. Independent predictive factors for survival were performed with the Cox regression method model using the backward option. All statistical analyses were performed using the SPSS software, version 10.5 (SPSS, Chicago, IL). Differences were considered to be significant at an alpha risk of 5%.
Results There were 119 men and 18 women with a mean age of 64 years (range, 47 to 81); their clinicopathologic characteristics are shown in Table 1. All patients had squamous cell
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Table 1. Clinicopathologic Characteristics of 137 Patients With Submucosal Esophageal Cancer Characteristics
Values 64 8
Age at surgery, years Sex Male Female Tumor location Upper thoracic Mid thoracic Lower thoracic Histology SCC Tumor differentiation Well Moderate Poor Unknown Depth of submucosal invasion SM1 SM2 SM3 Pathologic N category pN0 pN1, 1–2 LN pN2, 3–6 LN pN3, >6 LN Pathologic M category pM0 pM1 Resection category R0
119 (86.9) 18 (13.1) 26 83 28 137 (100) 17 61 43 16 32 59 46 90 41 6 0 133 4 137 (100)
Values are mean SD, n (%), or n. LN ¼ lymph node; submucosal.
SCC ¼ squamous cell carcinoma;
SM ¼
carcinoma. A complete macroscopic and microscopic resection of the primary tumor (R0 resection) was achieved in all patients, of whom 41 underwent three-field lymphadenectomy and 90 underwent two-field lymphadenectomy. There were 4 patients with pM1 stage because of M1 lymph node metastasis. The median number of resected lymph nodes was 35 (range, 15–78). The rate of lymph node metastasis increased stepwise according to the depth of wall penetration (Table 2). Of 46 patients with SM3 invasion, 23 (50.0%) had lymph node metastasis. Table 2. Depth of Tumor Infiltration and Rate of Lymph Node Metastasis in Submucosal Esophageal Cancer Tumor Depth
n
pNþ
p Value
SM1 SM2 SM3
32 59 46
6 (18.8) 18 (30.5) 23 (50.0)
. 0.3196 0.0082
Values are n (%). pN ¼ pathologic node;
SM ¼ submucosal.
Table 3 shows the distribution of metastatic lymph nodes as related to the locations of esophageal tumors. With upper thoracic esophageal cancers, metastatic lymph nodes were almost always detected in the cervical or upper thoracic regions. With mid esophageal cancers, there was a wide distribution of cervical, thoracic, and abdominal lymph nodes. With lower esophageal cancers, cervical or upper thoracic lymph node involvement was not detected. The mean follow-up period for all patients was 71 months; 30 patients (21.9%) had recurrence after esophagectomy. The patterns of recurrence according to the depth of invasion are shown in Table 4. Recurrence occurred in only 3 patients (9.4%) with SM1 carcinoma, and all recurrences were in the regional lymph nodes (ie, lymph nodes in areas inside the operative field) whereas recurrence was observed in 11 patients (18.6%) with SM2 carcinoma, of which 8 were limited to regional lymph nodes. Distant metastasis occurred when the tumors had infiltrated into deeper layers beyond SM1 and occurred most frequently with SM3 carcinomas. Local recurrence developed in none of the patients with SM carcinoma in our study. Among all patients, except those who died of esophageal cancer, there were 26 (21.8%) with metachronous cancer. The sites of the other primary malignancies were the head and neck in 8 patients, lung in 7 patients, stomach in 3 patients, and other areas in 10 patients. The 5-year and 10-year cause-specific survival rates were 96.2% and 96.2% for SM1 carcinoma, 92.2% and 89.9% for SM2 carcinoma, and 68.6% and 68.6% for SM3 carcinoma, respectively (Fig 1A). The 5-year and 10-year overall survival rates were 83.3% and 73.7% for SM1 carcinoma, 83.5% and 73.7% for SM2 carcinoma, and 58.1% and 54.9% for SM3 carcinoma, respectively (Fig 1B). Comparisons of overall survival among patients with SM1 or SM2 carcinoma showed no significant difference (p ¼ 0.565); therefore, the prognoses of patients with SM1/ SM2 versus SM3 was analyzed. On univariable analysis, tumor size (p ¼ 0.3076), tumor differentiation (p ¼ 0.9286), and angiolymphatic invasion (p ¼ 0.7156) had no effect on survival. Besides depth of submucosal invasion (p ¼ 0.0030), overall survival was significantly influenced by pathologic lymph node status (p ¼ 0.0467) and tumor location (p ¼ 0.0038). On multivariable survival analysis using the Cox proportional hazards model, significant correlations were noted between overall survival and each of depth of submucosal invasion (p ¼ 0.003) and tumor location (p ¼ 0.007). However, there was no significant correlation between overall survival and pathologic lymph node status (Table 5).
Comment The main finding of this study is that a depth of invasion deeper than SM1 signified higher rates of recurrence and distant metastasis. However, the prognoses of SM2 patients (5-year survival 83.3%) were similar to those of SM1 patients (5-year survival 83.3%), whereas the prognoses of
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Table 3. Primary Tumor Location and Lymph Node Metastasis in Patients With Submucosal Esophageal Cancer Lymph Node Metastasis Tumor Location Upper thoracic (n ¼ 7) Mid thoracic (n ¼ 28) Lower thoracic (n ¼ 12)
Cervical
Upper Thoracic
Mid Thoracic
Lower Thoracic
Abdominal
3 (43) 1 (4) 0 (0)
5 (71) 8 (29) 0 (0)
0 (0) 5 (18) 1 (8)
0 (0) 6 (21) 3 (25)
1 (14) 15 (54) 10 (83)
Values are n (%).
SM3 patients (5-year survival 58.1%) were significantly worse than for patients with more superficial submucosal invasion, and were closer to those of patients with locally advanced disease. Only 3 patients with SM1 (9.4%) had recurrence, whereas 11 SM2 patients (18.6%) had recurrence. However, the 5-year survival rate for patients with SM2 was identical to that of patients with SM1, possibly because of death due to other causes such as primary malignancy and the relatively good prognosis in patients with SM2. Of 8 patients with SM2 who had regional lymph node recurrence, 3 are still alive after having received additional chemoradiation therapy or surgery (7 to 11 years after regional lymph node recurrence); such episodes may suggest comparatively good prognoses in patients with SM2. Conversely, the poor prognosis of SM3 esophageal cancer can be explained by anatomic and oncologic features of the submucosal esophageal cancer. The esophageal lymphatic anatomy in the mucosa and submucosa was recently found to be nonhomogeneous by using D2-40 immunohistochemical staining. In the submucosa, lymphatics appear to be concentrated in the deep submucosa and have direct connections to more central lymphatic channels [20, 21]. Therefore, increasing the depth of submucosal invasion leads to greater risks of regional or distant lymph node metastases; that is considered to be one of the reasons why deep submucosal invasion is associated with poor survival. In terms of oncologic features, various features such as the expression of metalloproteinases, as well as proteases such as trypsin, are involved in neovascularization and tumorinduced proteolysis. These enzymes have been found to be expressed at higher levels in tumors that invade Table 4. Depth of Tumor Infiltration and Recurrence Patterns in Submucosal Esophageal Cancer Tumor Depth SM1 (n ¼ 32) SM2 (n ¼ 59)
n (%)
Recurrence Patterns (n)
3 (9.4)
Lymph node (3) (Regional lymph node: 3) Lymph node (10) (Regional lymph node: 8) Distant (1) Lymph node (8) (Regional lymph node: 7) Distant (10) .
11 (18.6)
SM3 (n ¼ 46)
16 (34.8)
Total (n ¼ 137)
30 (21.9)
SM ¼ submucosal.
deeper into the submucosa [22–24]; their expression may be associated with the increased malignant potential of SM3 esophageal squamous cell carcinomas. What constitutes an adequate extent of lymphadenectomy during surgery for submucosal esophageal cancer is controversial. Some studies recommended extended three-field lymphadenectomy for all patients with early tumors, irrespective of tumor location and histologic type, because lymph node metastasis will be found relatively frequently in the upper mediastinum or cervical region [25, 26]. Conversely, dissection of recurrent nerve and cervical nodes may impair swallowing functions, which can reduce the postoperative quality of life [8]. In the present study, an analysis of the distribution of lymph node metastases according to the tumor location showed that, in patients with lower esophageal carcinoma, neck and upper thorax lymph node metastasis is extremely rare. In terms of an adequate extent of lymph node dissection, cervical lymph node dissection may be avoidable for patients with lower-third superficial esophageal cancers. A second novel finding in this study is that patients with upper thoracic superficial esophageal carcinoma have significantly lower survival expectancies than do patients with mid or lower thoracic superficial esophageal carcinoma. Prognosis has not been reported to be influenced by tumor location; in particular, no studies to evaluate the prognosis of superficial esophageal carcinoma by the primary site have been performed to the best of our knowledge [15, 27, 28]. Of 26 patients with upper thoracic esophageal carcinoma, cervicothoracic lymph node metastasis occurred in 7 (27%), as compared with 8 of 111 patients with mid or lower thoracic esophageal carcinoma (7%) who had cervicothoracic lymph node metastasis. Complete dissection of the cervicothoracic nodes around the upper thoracic esophagus is technically difficult, which may be the reason for the poor prognosis of upper thoracic superficial esophageal cancer patients. In general, lymph node metastasis is widely characterized as being associated with worse survival outcomes in patients with submucosal esophageal cancer [6, 15, 29, 30]. Although lymph node metastasis was previously identified as a prognostic factor on univariable and multivariable analysis, it was not of prognostic value for the SESCC patients in the present study. In a recent study of submucosal esophageal cancer, no difference in survival was observed between patients with positive lymph node metastasis and those without [31]. The investigators in that study considered that the extent of lymph node
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Fig 1. (a) Cause-specific survival rates as a function of tumor depth in 137 patients who underwent primary surgical resection for submucosal (SM) thoracic esophageal squamous cell carcinoma. (b) Overall survival rates as a function of tumor depth in 137 patients who underwent primary surgical resection for submucosal thoracic esophageal squamous cell carcinoma. The SM3 carcinoma (broken lines) had a poorer outcome than SM1 (dotted lines) or SM2 (solid lines) carcinoma (p ¼ 0.003).
dissection by esophagectomy was different from that in most previous studies that included limited lymphadenectomies such as transhiatal esophagectomy. In the present study, the 5-year overall survival rates were 83.6% for SM1/2 with positive lymph node metastasis and 82.7% for SM1/2 with negative lymph node
metastasis, and there was no significant difference in prognosis between these two groups. Conversely, the 5-year overall survival rate of SM3 was 73.7% for nodenegative cases, but 41.7% for node-positive cases, indicating a significantly poorer prognosis for nonpositive cases (p ¼ 0.0311). As we have mentioned, SM1/2 and
Table 5. Univariable and Multivariable Analysis of Prognostic Factors for Overall Survival Multivariable Analysis Variable Age, years <65 65 Tumor size, cm <5 5 Tumor differentiation Well or moderate Poor Angiolymphatic invasion Present Not present pN status pN >1 pN0 Depth of SM invasion SM3 SM1/2 Tumor location Upper thoracic Mid, lower thoracic CI ¼ confidence interval;
n
5-Year OS
p Value
74 63
78.1% 70.4%
0.5603
95 42
74.3% 73.3%
0.3076
78 43
74.7% 70.0%
0.9286
86 45
71.8% 81.0%
0.7156
46 85
62.7% 81.1%
46 91 26 111 HR ¼ hazard ratio;
HR
95% CI
p Value
0.0467
1.567
0.831–2.958
0.165
58.1% 83.4%
0.0030
2.513
1.373–4.606
0.003
56.0% 79.2%
0.0038
2.433
1.184–4.628
0.007
OS ¼ overall survival;
pN ¼ pathologic node;
SM ¼ submucosal.
SM3 esophageal cancer have different anatomic and oncologic features. We suggest that these differences may explain why many SM1/2 carcinomas remain local diseases, even though the cases are positive for lymph node metastasis. However, when the depth of invasion has progressed to SM3, positivity for lymph node metastasis indicates that the esophageal carcinoma is progressing to systemic disease. We therefore inferred that prognosis would be significantly poorer for SM3 with lymph node metastasis. Based on these considerations, we view lymph node metastasis as a prognostic factor in SM3 carcinoma, but not in SM carcinoma as a whole. Moreover, given that patients with lymph node metastasis have been undergoing postoperative adjuvant chemotherapy since 2005, and that long-term follow-up visits help detect new malignancies, may dampen the influence of lymph node metastasis on survival. A limitation of this study is that it was a singleinstitution investigation that represented a highly selected population (although it spanned more than 20 years). As it was a surgical series, patients with submucosal cancers that were not medically operable were not represented. In conclusion, we found that upper thoracic or SM3 esophageal squamous cell carcinomas have a poor prognosis. A recent randomized study suggested that neoadjuvant chemotherapy with cisplatin and 5fluorouracil followed by surgery improved overall survival of patients with clinical stage II or III esophageal squamous cell carcinoma, including T1b [6]. Although determining the depth of submucosal invasion is difficult, neoadjuvant chemotherapy may improve the prognosis of SESCC patients suspected of having deeply infiltrative submucosal lesions or tumors located in the upper thoracic esophagus. Further prospective clinical trials are required to assess the efficacy of neoadjuvant therapy for these patients.
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8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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The Thoracic Surgery Foundation: For 29 Years, Turning Today’s Research Into Tomorrow’s Patient Care Our patients don’t follow the details of our research. They don’t discuss unexpected breakthroughs or technical setbacks. They are not always aware of how changes in health care policies impact research funding and lab time. Nonetheless, the advances we make in cardiothoracic surgery touch each and every one of them. New surgical techniques and potent new drugs improve patient health and extend patient lives. The Thoracic Surgery Foundation (TSF) is a pivotal force for growth and vitality in cardiothoracic surgery, especially for research and academic career development. TSF was first established in 1988 as a 501(c)(3) not-for-profit charitable foundation with support from the four major thoracic surgery organizations—the American Association for Thoracic Surgery, The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and the Western Thoracic Surgical Association. On October 1, 2014, TSF became the official charitable arm of The Society of Thoracic Surgeons. The foundation represents thoracic surgery in the United States and its research and educational initiatives support the broad spectrum of thoracic surgery. The mission of TSF is to foster the development of surgeon scientists in cardiothoracic surgery; increasing knowledge and innovation to benefit patient care.
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
Funding basic biomedical research to expand our understanding of thoracic surgery is vitally important. Still, it’s only half the battle. The results of such research must be successfully transferred to patient care. There is a compelling need to continue to develop the skills of cardiothoracic surgeons as scientists and as health policy leaders. TSF is an organization that is having a steering effect on cardiothoracic surgery through the sponsorship of research projects and the education of surgeons in health care policy. For 29 years, TSF support has enabled many young cardiothoracic surgeons to develop successful, independent research careers and improve the care of our patients. To date, TSF has funded 180 cardiothoracic surgery research grants, fellowships, and simulation awards, and funded more than 285 Alley-Sheridan Scholarships, and 25 travel awards. Because of your support, many of these individuals are now leaders in the cardiothoracic surgery community. This is a TSF legacy in which we can all take pride. Please help TSF continue its legacy by making a donation today. Visit www.thoracicsurgery foundation.org or contact Priscilla Kennedy, TSF Executive Director, at 312-202-5868, or by e-mail at [email protected].
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