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Esophageal carcinoma
Esophageal carcinoma The unusual variants The clinical behavior and response to therapy of rare histologic variants of esophageal carcinoma are unclear. To evaluate the results of therapy in this group the records of 29 patients treated between 1949 and 1991 with primary rare histologic variants of esophageal carcinoma were retrospectively reviewed. This group represented 1.2 % of 2454 cases of esophageal carcinoma treated between 1949 and 1991 and included mucoepidermoid (n = 14), small-cell (n = 12), adenoid cystic (n = 2), and carcinosarcoma (n = 1) carcinomas. Treatment for localized disease consisted of esophagectomy in five of seven patients with mucoepidermoid carcinoma, two of six patients with small-cell carcinoma; two of two patients with adenoid cystic carcinoma, and one of one patient with carcinosarcoma. Patients with stage IV mucoepidermoid carcinoma were treated predominately with radiation therapy (5/7). The majority of small cell carcinomas were treated with multiagent chemotherapy (10/12). The 1- and 3-year disease-specific survivals were 54 % and 9 % for mucoepidermoid carcinoma (median survival, 5 months) and 16% and 0% for small-cell carcinoma (median survival, 7 months), respectively. Patients with stage III mucoepidermoid carcinoma (median survival, 20.5 months) compared with those with stage III small-cell carcinoma (median survival, 6.2 months) had a significantly longer duration of survival (p < 0.05). Distant disease was present in 86 % of patients in whom recurrence developed after esophagectomy Esophagectomy is standard therapy for localized carcinomas of the esophagus. SmaIIcell carcinoma appears to be a more aggressive variant of carcinoma and is most commonly treated with chemotherapy. (J THoRAc CARDIOVASC SURG 1994;108:1138-46)
Michael D. Lieberman, MD, Dido Franceschi, MD, Benjamin Marsan, MD, and Michael Burt, MD, PhD, New York, N.Y.
Uusual variants of esophageal carcinoma include adenoid cystic, carcinoid, carcinosarcoma, choriocarcinoma, mucoepidermoid, and small-cell carcinoma. These uncommon tumors represent fewer than 1% of all esophageal malignancies in a large collective series from Japan.' The clinical behavior and response to therapy of rare histologic variants of esophageal carcinoma are unclear. This study reviewed the Memorial Hospital experience with rare carcinomas of the esophagus. From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, N.Y. Received for publication March 2, 1994. Accepted for publicationJuly 28, 1994. Address for reprints: Michael Burt, MD, PhD, Memorial SioanKetteringCancer Center, 1275 York Ave., New York, NY 10021. Copyright @ 1994 by Mosby-Year Book, Inc. . 0022-5223/94 $3.00 + 0 12/1/59497
1 1 38
Methods A computerized tumor registry of 2454 patients with the diagnosis of esophageal carcinoma treated at Memorial SioanKettering Cancer Center between 1949 and 1991 was reviewed to obtain the records of 29 patients (1.2% of all esophageal cancers) with variants of esophageal carcinoma. The histologic variants included mucoepidermoid (n = 14), small-cell (n = 12), adenoid cystic (n = 2), and carcinosarcoma (n = 1) carcinomas. Patient records were retrospectively reviewed for demographics, presenting symptoms, diagnostic modalities, disease stage, treatment, morbidity, recurrence, and survival. Survival was analyzed by the Kaplan-Meier method? and comparison of survival was analyzed by log-rank analysis-' Significance was defined as p < 0.05.
Results Demographics, clinical presentation, and treatment. Mucoepidermoid carcinoma (n = 14) was the most common variant of esophageal carcinoma encountered in the series. The median age of the patients was 60 years (range, 44 to 69 years) with a sex distribution of nine men
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Table I. Esophageal mucoepidermoid carcinoma: treatment and survival Patient age,sex
Stage
65,M
III
Middle
66, F
III
Middle
69,M
III
Distal
63,M
III
Proximal
57, F 44, M 58,M 63,M 49,M
III III III IV IV
Middle Distal Distal Distal Middle
65,F 44,M 51,M 52,M 62,F
IV IV IV IV IV
Distal Distal Distal Distal Middle
Location
Site of recurrence or metastases
Treatment
Esophagectomy, preop. XRT (3000 rad) Esophagectomy, postop. XRT (5500 rad), CDDP+ VCR + B Esophagectomy, 5-FU + A + MITO Esophagectomy, laryngectomy + postop. XRT (4400 rad) Esophagectomy Bypass + 5-FU + A + MITO XRT (6120 rad) XRT (6000 rad) XRT (4000 rad), 5-FU + A + MITO, CDDP+VCR XRT (5000 rad) XRT (6000 rad), 5-FU XRT (4500 rad) Esophagectomy Laser, CDDP + VCR, 5-FU + VB
Survival months, status
2,DPO Local, bone Pleura, pericardium
54, DOD
Liver, peritoneal
22, DOD
Local, liver
19, DOD
Local Persistent Bone, peritoneal Liver Bone, cervical aortic nodes
20, DOD 4, DOD 26, DOD 8, DOD 7, DOD
Lung, liver Bone, scalene node Liver Liver Liver
4, DOD 4,AWD 3, DOD 0.16, DPO 13, DOD
XRT, Radiation therapy; DPO, died postoperatively; CDDP, cisplatin; VCR, vincristine; B, bleomycin; DOD, dead of disease; 5-FU, 5-f1uorouracil; A, Adriamycin (doxorubicin hydrochloride); MjTO, mitomycin; AWD, alive with disease; VB, vinblastine.
and fivewomen. The most common presenting symptoms were dysphagia (93%) and weight loss (71%). The duration of symptoms was 1 to 6 months. Most patients had a history of smoking tobacco (79%) and alcohol consumption (57%). Diagnosis was established by esophagoscopy (100%) and barium esophagogram (79%). The carcinomas were equally divided into stages III and IV. The primary site included one proximal, fivemiddle, and eight distal lesions. Most of the patients with stage III disease had T4 findings (5/7) and nodes with positive findings (4/7). All patients with stage IV disease had nodes with positive findings. The sites of metastases and treatment modalities are provided in Table I. The most common sites of metastases included liver (5/7), bone (2/7), and cervical lymph nodes (2/7). Treatment included esophagectomy (6/14), radiation therapy (9/14), and chemotherapy (6/14). The median age for patients with small-cell carcinoma (n = 12) was 63 years (range, 40 to 75) with a male to female ratio of 5:1,Presenting symptoms were dysphagia (92%), weight loss (67%), and gastrointestinal bleeding (25%). Symptoms were present from 1 to 13 months before diagnosis. A history of smoking and heavy alcohol use was present in 92% and 83% of patients, respectively. Carcinomas were evenly divided into stages III and IV.
The primary site was located in the middle (4/12) and distal (8/12) esophagus. Table II illustrates metastatic sites and treatment modality. Metastatic sites included bone marrow 0/6), liver Oj6), adrenal (1/6),andlymph node (1/6). Treatment included esophagectomy (3/12), chemotherapy (10/12), and radiation therapy (4/12). Both patients (66-year-old woman, 58-year-old woman) with adenoid cystic carcinoma had presenting symptoms of dysphagia and weight loss. One patient had a stage II distal lesion and the other had a stage III middle esophageal cancer. Both tumors were diagnosed with endoscopy and treated with esophagectomy. One patient had a stage II middle esophageal carcinosarcoma with presenting symptoms of dysphagia, which was diagnosed by endoscopy and treated by esophagogastrectomy. Survival. The overall and disease-specific median survivals for 14 patients with mucoepidermoid carcinoma were 6.5 months and 7.0 months, respectively. The median disease-specific survival for patients with stage III disease was 20.5 months compared with 3.7 months for patients with stage IV disease (p < 0.05). The median disease-specific survival for six patients who underwent esophagectomy was 21 months. However, two of the patients died of postoperative complications. Four
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Table II. Esophageal small-cell carcinoma: treatment and survival Patient age, sex
Stage
68,M 68,M 52,M
III III III
Distal Distal Distal
73, F
III
Middle
70,M 46,M
III III
Distal Distal
63,M 59, F 58, F 63,M 40,M
IV IV IV IV IV
Distal Middle Middle Distal Middle
75,M
IV
Lower
Location
Site of recurrence or metastases
Treatment CTX+A+VCR CDDP+VP-16 CTX+PR XRT (3000 rad) CDDP+ VP-16 XRT (1500 rad) Esophagectomy Esophagectomy + CTX + A + VCR + CDDP CTX+A+VCR CTX+A+VCR CTX+A+VCR CTX+A+VCR CTX+5-FU XRT (4800 rad) Esophagectomy
Survival months, status
Persistent
1O.0,AWD 6.5, DOD
Liver Bone
5.0, DOD 8.5, DOD
Liver
2.0, DPO 24.0, DOD
Bone, liver, bone marrow Bone marrow Bone marrow Liver, adrenal Cervical lymph node Liver
0.5, DOD 1.3,DOD 5.6, DOD 1.3, DOD 10.3, DOD 1.4,DPO
CTX, Cytoxan (cyclophosphamide); A, Adriamycin(doxorubicin hydrochloride); VCR, vincristine; AWD, alivewith disease; CDDP, cisplatin; VP-16, etoposide; DOD, dead of disease; PR, prednisone; XRT, radiation therapy; DPO, died postoperatively; 5-FU, 5-fluorouracil.
patients whose lesions were unresectable had a median survival of 4 months. Survival ranged from 7 to 26 months for three patients treated with radiation therapy and chemotherapy. One patient treated with laser therapy and multiagent chemotherapy survived 13 months with stage IV disease. Both the overall and disease-specific median survivals for 12 patients with small-cell carcinoma were 5.2 months. The median disease-specific survival for patients with stage III disease was 6.2 months compared with 2.0 months for patients with stage IV disease (p = not significant). Survival ranged from 0.5 to 10 months for five patients treated with chemotherapy and from 1 to 10 months for four patients administered chemotherapy and radiation therapy, and was 24 months for esophagectomy and chemotherapy. Two patients died postoperatively after esophagectomy. Two patients were treated with an esophagectomy for adenoid cystic carcinoma. One patient died of a postoperative complication, and the second patient, who had stage II disease, survived 73 months before death of recurrence. The only patient with carcinosarcoma (stage II) was treated by esophagectomy and is disease-free at 10 months. Log-rank analysis demonstrated the significance of stage and histologic findings on overall survival. Patients with stage III (median survival, 8.9 months) compared with stage IV (median survival, 3.7 months) disease had significantly longer duration of survival (p < 0.01). Patients with stage III mucoepidermoid carcinoma
a
(median survival, 20.5 months) compared with patients with stage III small-cell carcinoma (median survival, 6.2 months) had a significantly longer duration of survival (p < 0.05). However, patients with stage IV mucoepidermoid Or small-cell carcinoma had equally poor outcomes, with median survivals of 3.7 and 2.0 months, respectively (Fig. 1). Recurrence. All patients (n = 5) with stage III mucoepidermoid carcinoma who survived initial curative treatment died within 6 months of recurrence. The sites of recurrence were local in 60% and distant in 80%. Distant sites of recurrence included liver (n = 2), lung or pleura (n = 2), peritoneum in = 2), and bone (n = 2). Local recurrence was treated with radiation therapy in two of three patients and the remaining patient had a resection of an anastomotic recurrence with colon interposition. One half of the patients with distant metastases were unsuccessfully treated with chemotherapy. Stage III disease was documented in 6 of 12 patients with small-cell carcinoma. Two patients were treated with esophagectomy. One patient died of a perioperative complication, and liver metastases developed at 16 months in a second patient who was treated with chemotherapy but died at 24 months. Two patients treated with chemotherapy and radiation therapy died within 2 months of treatment of widespread distant metastases. Two patients were treated primarily with chemotherapy. One patient died at 6.5 months of aspiration pneumonia caused by persistent local disease, and the remaining patient is alive with persistent local disease. Lung and liver metastases developed in the patient with
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1
1 14 1
Proportion Surviving
0.9 0.8
I---<
0.7 0.6 0.5 0.4
H
0.3
0.2 0.1
o
o
r, 12
24
36
48
60
TIme (mos.) I+MEStage3 .MEStage4 +SCStage3 -SCStage41
Fig. 1. Overall actuarial survival of patients with mucoepidermoid (ME, n = 14) or small-cell (SC; n = 12) carcinoma of esophagus according to stage.
stage II adenoid cystic carcinoma at 67 months and this patient had a 6-month recurrence-to-death interval with no further therapy. Perioperative morbidity and mortality. In this series 16 patients underwent surgical exploration: 12 esophagectomy (Ivor Lewis, 10; transhiatal, I; left thoracotomy, I), 3 biopsy, and I a bypass procedure. Five patients died in the early postoperative period. All deaths were in patients who underwent Ivor Lewis esophagectomy. Operative mortality according to histologic type included 66% of small-cell carcinomas, 50% of adenoid cystic carcinomas, and 33% of mucoepidermoid carcinomas. The tumor stage, site, histologic type, year of treatment, cause of death, and treatment of complication are provided for each perioperative death in Table III. A major perioperative complication was encountered in II of 16 patients. The majority of complications occurred with esophagectomy (9/12) compared with bypass or biopsy (2/4). Complications included anastomotic leak (3/13), pneumonia 0/16), intraabdominal bleeding that necessitated incidental splenectomy (1/16), tracheopleural fistula (1/16), wound infection (1/16), myocardial infarction (1/16), and anastomotic stricture (3/13). The only patient who required reoperation had an anastomotic leak that necessitated esophageal diversion and drainage of an empyema. All anastomotic strictures were treated successfully in an outpatient setting with dilation. Discussion Unusual carcinomas constitute 1.2% of 2454 esophageal carcinomas treated at Memorial Hospital between
1949 and 1991. The variant histologic types are similar to squamous cell carcinoma and adenocarcinoma of the esophagus with respect to clinical presentation, method of diagnosis, and stage of disease at presentation. Most patients are in the seventh decade of life, male, and have a history of tobacco use, dysphagia, weight loss, and an advanced-stage esophageal malignancy at presentation. With the exception of small-cell carcinoma, treatment and overall survival of patients with the rare carcinomas are similar to those for squamous cell and adenocarcinoma of the esophagus. At Memorial Hospital a review of 258 patients who underwent resection for esophageal carcinoma between 1985 and 1991 was associated with a 27-month median overall survival for adenocarcinoma and a 22-month median overall survival for squamous cell carcinoma of the esophagus (unpublished data). These survivals are comparable to the 20.5-month survival for patients with resectable mucoepidermoid carcinoma of the esophagus. Outcome is most strongly influenced by extent of disease defined by TNM stage." Small-cell carcinoma appears to be a more aggressive variant of carcinoma manifested by diminished overall survival. Treatment is chemotherapy oriented for small-cell carcinoma, whereas the other tumors are most often treated by resection. The unusual variants appear to behave like squamous cell carcinoma and adenocarcinoma of the esophagus with respect to the propensity for both local and distant recurrence." The histogenesis of mucoepidermoid carcinoma of the esophagus is from the tubuloalveolar mucous glands of the submucosa.v'' The prevalence of the tumor is 0.4% in this series, which is similar to the prevalence in the report
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Table III. Perioperative mortality according to tumor characteristics and cause of death Patient age.sex 65, 52, 70, 75,
M M M M
58, F
Histologic type
Stage
Site
Operation date
Cause of death
Treatment
ME ME SC SC
III IV III IV
Middle Distal Distal Distal
1971 1979 1975 1986
Tracheopleural fistula Acute MI Pneumonia/sepsis Anastomotic leak/sepsis
AC
III
Middle
1986
Aspiration/sepsis
Thorocostomy tube Vasopressors Antibiotics/ventilator Esophageal diversion and drainage Antibiotics/ventilator
ME, Mucoepidermoid carcinoma; MI, myocardial infarction; SC, small-cell carcinoma; AC, adenoid cystic carcinoma.
of Suzuki and Nagayo! of 0.4% of 11,932 patients with malignant esophageal neoplasms. Twenty-two cases of mucoepidermoid carcinoma of the esophagus have been reported in the English literature. 5- 12 The results were pooled and analyzed for overall survival. Most patients were male (78%), the median age was 60 years, and presentation included dysphagia and weight loss. Primary treatment was esophagectomy (91%) or radiation therapy (9%). Of the 20 patients who underwent resection, 4 died perioperatively and the remaining patients had a median overall survival of 12 months (Fig. 2). The two patients treated with radiation therapy died within 7 months of diagnosis. Patients who had recurrences died of distant disease. This study demonstrated a longer duration of survival for patients who underwent esophagectomy (median disease-specific survival of 21 months). However, most patients had recurrences at distant sites and died. The difference in survival noted between this study and the small combined series probably reflects differences in patient selection for esophagectomy. The prevalence of small-cell carcinoma ranges from 0.02% to 2.4% of malignant esophageal tumors.P'" The cell of origin of small-cell carcinoma of the esophagus is from the argyrophilic cells of the epithelial basal layer. I 7 The tumors stain positive by Grimelius and neuron-specific enolase and demonstrate neurosecretory granules by electron microscopy. Grossly, most tumors are fungating lesions located in the distal two thirds of the esophagus. 16 Most patients are first seen with dysphagia and weight loss. Although tumors may stain for various hormones (adrenocorticotrophic hormone and calcitonin), detection of secreted hormones or clinical syndromes is rare. 17-21 A total of 124 cases of small-cell carcinoma of the esophagus have been previously reported in the English literature and are available for survival analysis. lO, 13, 15-44 The treatment for these patients included esophagectomy (46%), chemotherapy (14%), radiation (6%), chemotherapy and radiation (14%), esophagectomy and chemotherapy (5%), and no therapy (17%). Raw data from these patients were analyzed to generate survival curves by the Kaplan-Meier method.? and comparisons were determined by log-rank test.' The median
overall survival was 5 months. Figure 3 depicts the actuarial survival of the 107 patients who received therapy. Descending order of duration of overall survival was esophagectomy plus chemotherapy (n = 6; median survival, 28 months), chemotherapy and radiation (n = 36; median survival, 8 months), esophagectomy (n = 57; median survival, 5 months), radiation therapy (n = 8; median survival, 2.5 months), and no therapy (n = 17; median survival, I month). Patients died of distant disease. This collected experience shows results similar to ours. Small-cell carcinoma is a highly aggressive carcinoma with a propensity for distant metastases at presentation or shortly thereafter. Primary therapy is chemotherapy. However, results reported in the literature and findings from this study suggest a survival advantage for patients who undergo resection plus chemotherapy. Adenoid cystic carcinoma arises in the tubuloalveolar ducts of the mucus glands of the submucosa.v 45, 46 The prevalence of adenoid cystic carcinoma of the esophagus ranges from 0.07% to 0.8% of cancers of the esophagus. I , 46 The patient typically is first seen with dysphagia. The tumor is grossly fungating and infiltrating and most commonly located in the middle third of the esophagus.f Thirty-eight of 50 reported cases that involved the esophagus are available for analysis. I ,6,45-58 The male-tofemale ratio was 2.5, and the median age was 62 years (range, 36 to 83). Metastases developed in 50% of patients, the majority of which were widespread to liver, lung, and brain. Five of the 38 patients had widespread metastases on presentation and died within 6 months of diagnosis after no therapy or incomplete chemotherapy. Five patients with locoregional disease were treated with radiation therapy: three died of disease at I to 21 months and two are without evidence of disease at 8 and 16 months. Twenty-eight (74%) patients underwent esophagectomy with a perioperative mortality rate of 21%. A Kaplan-Meier curve/ was generated for the 22 patients who survived esophagectomy (Fig. 4). The median survival was 24 months, and the 3-year survival was 35%. These results are discouraging relative to those of adenoid cystic carcinoma of the salivary gland for which 5-year
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Lieberman et at.
1 14 3
Proportion Surviving
1<»-----------------------_ 0.9 0.8
0.7
Median-12 mos
0.6 0.5 0.4 0.3 0.2 0.1
OL------'--------'---------'-----'------------' 48 60 o 12 24 36
Time (rnos) Fig. 2.· Overall actuarial survival of 16 patients who survived resection for primary mucoepidermoid carcinoma of esophagus (5-year survival; 18%). (Modified with permission from Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsberg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).) Proportion Surviving 1tiiil-'?"-----'ii'--'V'-------------------------,
0.9 0.8
0.7
0.6 0.5 0.4 0.3 0.2 0.1
o L--------J;-----------'--~==~~----~-~ 24 36 o 12 Time (rnos) ---&-
Radiation Rx (n-S)
--+- Resection (n-57)
--£-
Chemotherapy (n-36)
--'i1-
Resect
+
Chemo (n-6)
Fig. 3. Overall actuarial survival of 107 patients with primary small-cell carcinoma of esophagus who received radiation therapy, esophagectomy, chemotherapy, or esophagectomy and chemotherapy. (Modified with permission from Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsberg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).)
survival was 69% in 264 patients who underwent resection.59 Carcinosarcoma is an uncommon tumor with features of carcinoma and sarcoma. The most recent findings concerning the histogenesis of this tumor are that the sarcomatous elements arise by spindle cell metaplasia of squamous cell carcinoma/" The prevalence of carcinosarcoma in large series of esophageal malignancies ranges from 0.3% to 2.4%.10,61-63 In a review of the English literature, 73 cases of primary carcinosarcoma of the
esophagus were available for analysis. 62-n The initial clinical presentation is similar to that of squamous cell carcinoma with dysphagia (80%) and weight loss (61%) predominating. The locations of the tumors were 13% upper, 59% middle, and 28% lower third of the esophagus. Forty-five patients were available for survival analysis. One patient was treated with radiation therapy and seven patients died in the early postoperative period. The overall survival of 34 patients who underwent esophagectomy for primary carcinosarcoma (excluding early post-
1 14 4
The Journal of Thoracic and Cardiovascular Surgery December 1994
Lieberman et al.
Proportion Surviving
1
"J,
0.9 0.8
t----t
0.7
N-22
0.6 0.5 0.4
0.3 0.2
Median-24 mos
0.1
o
o
12
24
36
60
48
Time (mos) Fig. 4. Overall actuarial survival of 22 patients who survived resection for primary adenoid cystic carcinoma of esophagus. (Modified with permissionfrom Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsberg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).)
Proportion Surviving 1< r ' & ' v - - - - - - - - - - - - - - - - - - - - - - - - - - - - ,
0.9
0.8 0.7
0.6 0.5
0.4
0.3
N-34
0.2 0.1
o o
L-
~
12
__L
__'___
24
36
_'__
48
_
60
Time Fig. 5. Overall actuarial survivalof 34 patients who survived resection for primary carcinosarcoma of esophagus (5-year survival, 55%). (Modified with permission from Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsburg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).)
operative deaths) is illustrated in Fig. 5. The 5-year actuarial disease-specific survival for this group is 54%. Patients die of distant metastases to liver, brain, lung, and bone. Locoregional metastasis to lymph node is a less common event. However, a recent Japanese study tn = 20) reported a 5-year survival of 28% and lymph node involvement in 65% of patients who underwent esophagectomy and complete lymph node dissection."
Thus it remains unclear whether carcinosarcoma represents a more favorable histologic variant. On the basis of our experience and previously published data, we recommend esophagectomy for patients with locally confined mucoepidermoid, adenoid cystic, or carcinosarcoma of the esophagus. Treatment for smallcell carcinoma should include preoperative chemotherapy followed by esophagectomy for patients with
The Journal of Thoracic and Cardiovascular Surgery Volume 108, Number 6
only residual locoregional disease. Although this study reported a high operative mortality rate for the time period 1949 to 1991, presently the operative mortality rate at Memorial Hospital is 5% for carcinoma of the esophagus (unpublished data). Thus esophagectomy may be done with acceptable operative mortality in the treatment of carcinoma of the esophagus. REFERENCES I. Suzuki H, Nagayo T. Primary tumors of the esophagus other than squamous cell carcinoma: histologic classification and statistics in the surgical and autopsied material in Japan. Int Advances Surg Oncol 1980;3:73-109. 2. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:45781. 3. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observations of each patient: II-analysis and examples. Br J Cancer 1977;35:1-39. 4. Roth JA, Lichter AS, Putnam JB, Forastiere AA. Cancer of the esophagus. In: De Vita VT, Hellman S, Rosenberg SA, eds. Cancer: principlesand practice of oncology.4th ed. Philadelphia: JB Lippincott, 1993:776-817. 5. Kay S. Mucoepidermoid carcinoma of the esophagus: report of two cases. Cancer 1968;22:1053-9. 6. Bell-ThompsonJ, Haggitt RC, Ellis HR. Mucoepidermoid and adenoid cystic carcinomas of the esophagus. J THORAC CARDIOVASC SURG 1980;79:438-46. 7. Pascal RR, Clearfield HR. Mucoepidermoid (adenosquamous) carcinoma arising in Barrett's esophagus. Dig Dis Sci 1987;32:428-32. 8. Sasajima K, Watanabe M, Takubo K, et al. Mucoepidermoid carcinoma of the esophagus: report of two cases and review of the literature. Endoscopy 1990;22:140-3. 9. Weitzer S. Mucoepidermoid carcinoma of the esophagus: report of a case. Arch Pathol 1970;90:271-3. 10. Turnbull AD, Rosen P, Goodner JT, Beattie EJ. Primary malignant tumors of the esophagus other than typical epidermoid carcinoma. Ann Thorac Surg 1973;15:46373. II. Osamura RY, Sato S, Miwa M, Miwa T. Mucoepidermoid carcinoma of the esophagus. Am J Gastroenterol 1978;69:467-70. 12. Woodard BH, Shelburne JD, Vollmer RT, Postlethwait RW. Mucoepidermoid carcinoma of the esophagus: a case report. Hum Pathol 1978;9:352-4. 13. McKeown F. Oat-cell carcinoma of the oesophagus. J Pathol Bacteriol 1952;64:889-91. 14. Matsusaka T, WatanabeH, Enjoji M. Pseudosarcoma and carcinosarcoma of the esophagus. Cancer 1976;37:154655. IS. Isolauri J, Mattila J, Kallioniemi O. Primary undifferentiated small cell carcinoma of the esophagus: clinicopathologicaland flowcytometric evaluation of eight cases. J Surg OncoI1991;46:174-7. 16. Briggs JC, Ibrahim NBN. Oat cell carcinoma of the
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iguro S. Small-cell carcinoma of the esophagus: a case treated by chemotherapy. Endoscopy 1987;19:31-3. 37. Ignacio AG, Chintapalli K, Choi H. Primary oat cell carcinoma of the esophagus. Am J GastroenteroI1987;82:7881. 38. Sasajima K, Hayashi N, Yamashita K, Onda M, Takubo K. Oat cell carcinoma of the esophagus with multiple differentiation. J Clin GastroenteroI1988;10:667-71. 39. Eccles DM, Allan SG, Sang CTM, Cornbleet MA. Small cell carcinoma of the oesophagus: report of three cases and review of published cases. Thorax 1989;44:749-50. 40. Walker SJ, Steel A, Cullen MH, Matthews HR. Treatment of oesophageal small cell carcinoma by combined chemotherapy and surgical resection: report of cases and review of published cases. Thorax 1989;44:751-2. 41. Hussein AM, Feun LG, Sridhar KS, Benedetto P, Waldman S, Otrakji CL. Am J Clin OncoI1990;13:369-73. 42. Caldwell CB, Bains MS, Burt M. Unusual malignant neoplasms of the esophagus: oat cell carcinoma, melanoma and sarcoma. J THORAC CARDIOVASC SURG 1991;101:100-7. 43. Mulder LD, Gardiner GA, Weeks DA. Primary small cell carcinoma of the esophagus: case presentation and review of the literature. Gastrointest Radiol 1991;16:5-1O. 44. Hoda SA, Hajdu SI. Small cell carcinoma of the esophagus: cytology and immunohistology in four cases. Acta CytoI1992;36:113-29. 45. O'Sullivan JP, Cockburn JS, Drew CEo Adenoid cystic carcinoma of the oesophagus. Thorax 1975;30:476-80. 46. Epstein JI, Sears DL, Tucker RS, Eagan JW. Carcinoma of the esophagus with adenoid cystic differentiation. Cancer 1984;53:1131-6. 47. Petursson SR. Adenoid cystic carcinoma of the esophagus: complete response to combination chemotherapy. Cancer 1986;57:1464-7. 48. Nelms DC, Luna MA. Primary adenocystic carcinoma (cylindromatous carcinoma) of the esophagus. Cancer 1972;29:440-3. 49. Bergmann M, Charnas RM. Tracheobronchial rests in the esophagus: their relation to some benign strictures and certain types of cancer of the esophagus. J THORAC CARDIOVASC SURG 1958;35:97-104. 50. Pourzand A, Freant L, Levin R, Peabody J, Absolon K. Primary adenoid cystic carcinoma of the esophagus. J THORAC CARDIOVASC SURG 1975;69:785-9. 51. Kabuto T, Tanigushi K, Iwanaga T, et al. Primary adenoid cystic carcinoma of the esophagus. Cancer 1979;43:24526. 52. Rojas RAM, Vallacillo LA. Primary adenoid cystic carcinoma of the esophagus: report of one case and a review of the literature. Arch OtolaryngoI1959;70:197-201. 53. Sweeney EC, Cooney T. Adenoid cystic carcinoma of the esophagus. Cancer 1980;45:1516-25. 54. Jacobsohn WZ, Libson Y, Dollberg L. Adenoid cystic carcinoma of the esophagus. Gastrointest Endosc 1980;26: 102-4.
The Journal of Thoracic and Cardiovascular Surgery December 1994
55. Allard M, Farkouh E, Atlas H, Paquin JG. Primary adenoid cystic carcinoma of the esophagus. Can J Surg 1981; 24:405-6. 56. Kim JH, Lee MS, Cho SW, Shim CS. Primary adenoid cystic carcinoma of the esophagus: a case report. Endoscopy 1991;23:38-41. 57. Cerar A, Juteresek A, Vidmar S. Adenoid cystic carcinoma of the esophagus: a clinicopathologic study of three cases. Cancer 1991;67:2159-64. 58. Sakaurai H, Charoenkul V, Choi HH, et al. Unusual tumors of the esophagus. Surg Rounds 1993;52-6. 59. Spiro RH, Huvos AG, Strong EW. Adenoid cystic carcinoma: factors influencing survival. Am J Surg 1979;138: 579-84. 60. Takubo K, Tsuchiya S, Nakagawa H, Futatsuki K, Ishibashi I, Hirata F. Pseudosarcoma of the esophagus. Hum PathoI1982;13:503-5. 61. Iyomasa S, Kato H, Tachimori Y, Watanabe H, Yamagucchi H, Itabashi M. Carcinosarcoma of the esophagus: a twenty-case study. Jpn J Clin Oncol 1990;20:99-106. 62. Talbert JL, Cantrell JR. Clinical and pathologic characteristics of carcinosarcoma of the esophagus. J THORAC CARDIOVASC SURG 1963;45:1-12. 63. Xu L, Sun C, Wu L, Chang Z, Liu T. Clinical and pathological characteristics of carcinosarcoma of the esophagus: report of four cases. Ann Thorac Surg 1984;37:197-203. 64. Stout AP, Humphreys GH, Rottenberg LA. A case of carcinosarcoma of the esophagus. AJR Am J Roentgenol 1949;61:461-9. 65. Moore TC, Barrersby JS, Vellios F, Loehr WM. Carcinosarcoma of the esophagus. J THORAC CARDIOVASC SURG 1963;45:281-7. . 66. DeMarco AR, Leon W, Coleman WO, Welsh RA, Strug LH. Pseudosarcoma of the esophagus. J THORAC CARDIOVASC SURG 1965;49:188-93. 67. Scarpa FJ. Polypoid squamous carcinoma ofthe esophagus: report of a case and its implications for the histiogenesisof "carcinosarcoma" of the esophagus. Cancer 1966;19: 861-6. 68. Stener B, Kock NG, Pettersson S, Zetterlund B. Carcinosarcoma of the esophagus. J THORAC CARDIOVASC SURG 1967;54:746-50. 69. DeMeester TR, Skinner DB. Polypoid sarcomas of the esophagus. Ann Thorac Surg 1975;20:405-17. 70. Matsusaka T, Watanabe H, Enjoji M. Anaplastic carcinoma of the esophagus: report of three cases and their histiogenetic consideration. Cancer 1976;37:1352-8. 71. Osamura R Y, Watanabe K, Shimamura K, et al. Polypoid carcinoma of the esophagus: a unifying team for "carcinosarcoma" and "pseudosarcoma." Am J Surg Pathol 1978;2:201-8. 72. Miranda FJ, Kallas-Neto JA, DaCosta EA, Badan-Palhares FA. Carcinosarcoma of the esophagus. Int Surg 1980;65:463-7.
Michael D. Lieberman, MD, Dido Franceschi, MD, Benjamin Marsan, MD, and Michael Burt, MD, PhD, New York, N.Y.
Uusual variants of esophageal carcinoma include adenoid cystic, carcinoid, carcinosarcoma, choriocarcinoma, mucoepidermoid, and small-cell carcinoma. These uncommon tumors represent fewer than 1% of all esophageal malignancies in a large collective series from Japan.' The clinical behavior and response to therapy of rare histologic variants of esophageal carcinoma are unclear. This study reviewed the Memorial Hospital experience with rare carcinomas of the esophagus. From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, N.Y. Received for publication March 2, 1994. Accepted for publicationJuly 28, 1994. Address for reprints: Michael Burt, MD, PhD, Memorial SioanKetteringCancer Center, 1275 York Ave., New York, NY 10021. Copyright @ 1994 by Mosby-Year Book, Inc. . 0022-5223/94 $3.00 + 0 12/1/59497
1 1 38
Methods A computerized tumor registry of 2454 patients with the diagnosis of esophageal carcinoma treated at Memorial SioanKettering Cancer Center between 1949 and 1991 was reviewed to obtain the records of 29 patients (1.2% of all esophageal cancers) with variants of esophageal carcinoma. The histologic variants included mucoepidermoid (n = 14), small-cell (n = 12), adenoid cystic (n = 2), and carcinosarcoma (n = 1) carcinomas. Patient records were retrospectively reviewed for demographics, presenting symptoms, diagnostic modalities, disease stage, treatment, morbidity, recurrence, and survival. Survival was analyzed by the Kaplan-Meier method? and comparison of survival was analyzed by log-rank analysis-' Significance was defined as p < 0.05.
Results Demographics, clinical presentation, and treatment. Mucoepidermoid carcinoma (n = 14) was the most common variant of esophageal carcinoma encountered in the series. The median age of the patients was 60 years (range, 44 to 69 years) with a sex distribution of nine men
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Table I. Esophageal mucoepidermoid carcinoma: treatment and survival Patient age,sex
Stage
65,M
III
Middle
66, F
III
Middle
69,M
III
Distal
63,M
III
Proximal
57, F 44, M 58,M 63,M 49,M
III III III IV IV
Middle Distal Distal Distal Middle
65,F 44,M 51,M 52,M 62,F
IV IV IV IV IV
Distal Distal Distal Distal Middle
Location
Site of recurrence or metastases
Treatment
Esophagectomy, preop. XRT (3000 rad) Esophagectomy, postop. XRT (5500 rad), CDDP+ VCR + B Esophagectomy, 5-FU + A + MITO Esophagectomy, laryngectomy + postop. XRT (4400 rad) Esophagectomy Bypass + 5-FU + A + MITO XRT (6120 rad) XRT (6000 rad) XRT (4000 rad), 5-FU + A + MITO, CDDP+VCR XRT (5000 rad) XRT (6000 rad), 5-FU XRT (4500 rad) Esophagectomy Laser, CDDP + VCR, 5-FU + VB
Survival months, status
2,DPO Local, bone Pleura, pericardium
54, DOD
Liver, peritoneal
22, DOD
Local, liver
19, DOD
Local Persistent Bone, peritoneal Liver Bone, cervical aortic nodes
20, DOD 4, DOD 26, DOD 8, DOD 7, DOD
Lung, liver Bone, scalene node Liver Liver Liver
4, DOD 4,AWD 3, DOD 0.16, DPO 13, DOD
XRT, Radiation therapy; DPO, died postoperatively; CDDP, cisplatin; VCR, vincristine; B, bleomycin; DOD, dead of disease; 5-FU, 5-f1uorouracil; A, Adriamycin (doxorubicin hydrochloride); MjTO, mitomycin; AWD, alive with disease; VB, vinblastine.
and fivewomen. The most common presenting symptoms were dysphagia (93%) and weight loss (71%). The duration of symptoms was 1 to 6 months. Most patients had a history of smoking tobacco (79%) and alcohol consumption (57%). Diagnosis was established by esophagoscopy (100%) and barium esophagogram (79%). The carcinomas were equally divided into stages III and IV. The primary site included one proximal, fivemiddle, and eight distal lesions. Most of the patients with stage III disease had T4 findings (5/7) and nodes with positive findings (4/7). All patients with stage IV disease had nodes with positive findings. The sites of metastases and treatment modalities are provided in Table I. The most common sites of metastases included liver (5/7), bone (2/7), and cervical lymph nodes (2/7). Treatment included esophagectomy (6/14), radiation therapy (9/14), and chemotherapy (6/14). The median age for patients with small-cell carcinoma (n = 12) was 63 years (range, 40 to 75) with a male to female ratio of 5:1,Presenting symptoms were dysphagia (92%), weight loss (67%), and gastrointestinal bleeding (25%). Symptoms were present from 1 to 13 months before diagnosis. A history of smoking and heavy alcohol use was present in 92% and 83% of patients, respectively. Carcinomas were evenly divided into stages III and IV.
The primary site was located in the middle (4/12) and distal (8/12) esophagus. Table II illustrates metastatic sites and treatment modality. Metastatic sites included bone marrow 0/6), liver Oj6), adrenal (1/6),andlymph node (1/6). Treatment included esophagectomy (3/12), chemotherapy (10/12), and radiation therapy (4/12). Both patients (66-year-old woman, 58-year-old woman) with adenoid cystic carcinoma had presenting symptoms of dysphagia and weight loss. One patient had a stage II distal lesion and the other had a stage III middle esophageal cancer. Both tumors were diagnosed with endoscopy and treated with esophagectomy. One patient had a stage II middle esophageal carcinosarcoma with presenting symptoms of dysphagia, which was diagnosed by endoscopy and treated by esophagogastrectomy. Survival. The overall and disease-specific median survivals for 14 patients with mucoepidermoid carcinoma were 6.5 months and 7.0 months, respectively. The median disease-specific survival for patients with stage III disease was 20.5 months compared with 3.7 months for patients with stage IV disease (p < 0.05). The median disease-specific survival for six patients who underwent esophagectomy was 21 months. However, two of the patients died of postoperative complications. Four
1140
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Table II. Esophageal small-cell carcinoma: treatment and survival Patient age, sex
Stage
68,M 68,M 52,M
III III III
Distal Distal Distal
73, F
III
Middle
70,M 46,M
III III
Distal Distal
63,M 59, F 58, F 63,M 40,M
IV IV IV IV IV
Distal Middle Middle Distal Middle
75,M
IV
Lower
Location
Site of recurrence or metastases
Treatment CTX+A+VCR CDDP+VP-16 CTX+PR XRT (3000 rad) CDDP+ VP-16 XRT (1500 rad) Esophagectomy Esophagectomy + CTX + A + VCR + CDDP CTX+A+VCR CTX+A+VCR CTX+A+VCR CTX+A+VCR CTX+5-FU XRT (4800 rad) Esophagectomy
Survival months, status
Persistent
1O.0,AWD 6.5, DOD
Liver Bone
5.0, DOD 8.5, DOD
Liver
2.0, DPO 24.0, DOD
Bone, liver, bone marrow Bone marrow Bone marrow Liver, adrenal Cervical lymph node Liver
0.5, DOD 1.3,DOD 5.6, DOD 1.3, DOD 10.3, DOD 1.4,DPO
CTX, Cytoxan (cyclophosphamide); A, Adriamycin(doxorubicin hydrochloride); VCR, vincristine; AWD, alivewith disease; CDDP, cisplatin; VP-16, etoposide; DOD, dead of disease; PR, prednisone; XRT, radiation therapy; DPO, died postoperatively; 5-FU, 5-fluorouracil.
patients whose lesions were unresectable had a median survival of 4 months. Survival ranged from 7 to 26 months for three patients treated with radiation therapy and chemotherapy. One patient treated with laser therapy and multiagent chemotherapy survived 13 months with stage IV disease. Both the overall and disease-specific median survivals for 12 patients with small-cell carcinoma were 5.2 months. The median disease-specific survival for patients with stage III disease was 6.2 months compared with 2.0 months for patients with stage IV disease (p = not significant). Survival ranged from 0.5 to 10 months for five patients treated with chemotherapy and from 1 to 10 months for four patients administered chemotherapy and radiation therapy, and was 24 months for esophagectomy and chemotherapy. Two patients died postoperatively after esophagectomy. Two patients were treated with an esophagectomy for adenoid cystic carcinoma. One patient died of a postoperative complication, and the second patient, who had stage II disease, survived 73 months before death of recurrence. The only patient with carcinosarcoma (stage II) was treated by esophagectomy and is disease-free at 10 months. Log-rank analysis demonstrated the significance of stage and histologic findings on overall survival. Patients with stage III (median survival, 8.9 months) compared with stage IV (median survival, 3.7 months) disease had significantly longer duration of survival (p < 0.01). Patients with stage III mucoepidermoid carcinoma
a
(median survival, 20.5 months) compared with patients with stage III small-cell carcinoma (median survival, 6.2 months) had a significantly longer duration of survival (p < 0.05). However, patients with stage IV mucoepidermoid Or small-cell carcinoma had equally poor outcomes, with median survivals of 3.7 and 2.0 months, respectively (Fig. 1). Recurrence. All patients (n = 5) with stage III mucoepidermoid carcinoma who survived initial curative treatment died within 6 months of recurrence. The sites of recurrence were local in 60% and distant in 80%. Distant sites of recurrence included liver (n = 2), lung or pleura (n = 2), peritoneum in = 2), and bone (n = 2). Local recurrence was treated with radiation therapy in two of three patients and the remaining patient had a resection of an anastomotic recurrence with colon interposition. One half of the patients with distant metastases were unsuccessfully treated with chemotherapy. Stage III disease was documented in 6 of 12 patients with small-cell carcinoma. Two patients were treated with esophagectomy. One patient died of a perioperative complication, and liver metastases developed at 16 months in a second patient who was treated with chemotherapy but died at 24 months. Two patients treated with chemotherapy and radiation therapy died within 2 months of treatment of widespread distant metastases. Two patients were treated primarily with chemotherapy. One patient died at 6.5 months of aspiration pneumonia caused by persistent local disease, and the remaining patient is alive with persistent local disease. Lung and liver metastases developed in the patient with
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1
1 14 1
Proportion Surviving
0.9 0.8
I---<
0.7 0.6 0.5 0.4
H
0.3
0.2 0.1
o
o
r, 12
24
36
48
60
TIme (mos.) I+MEStage3 .MEStage4 +SCStage3 -SCStage41
Fig. 1. Overall actuarial survival of patients with mucoepidermoid (ME, n = 14) or small-cell (SC; n = 12) carcinoma of esophagus according to stage.
stage II adenoid cystic carcinoma at 67 months and this patient had a 6-month recurrence-to-death interval with no further therapy. Perioperative morbidity and mortality. In this series 16 patients underwent surgical exploration: 12 esophagectomy (Ivor Lewis, 10; transhiatal, I; left thoracotomy, I), 3 biopsy, and I a bypass procedure. Five patients died in the early postoperative period. All deaths were in patients who underwent Ivor Lewis esophagectomy. Operative mortality according to histologic type included 66% of small-cell carcinomas, 50% of adenoid cystic carcinomas, and 33% of mucoepidermoid carcinomas. The tumor stage, site, histologic type, year of treatment, cause of death, and treatment of complication are provided for each perioperative death in Table III. A major perioperative complication was encountered in II of 16 patients. The majority of complications occurred with esophagectomy (9/12) compared with bypass or biopsy (2/4). Complications included anastomotic leak (3/13), pneumonia 0/16), intraabdominal bleeding that necessitated incidental splenectomy (1/16), tracheopleural fistula (1/16), wound infection (1/16), myocardial infarction (1/16), and anastomotic stricture (3/13). The only patient who required reoperation had an anastomotic leak that necessitated esophageal diversion and drainage of an empyema. All anastomotic strictures were treated successfully in an outpatient setting with dilation. Discussion Unusual carcinomas constitute 1.2% of 2454 esophageal carcinomas treated at Memorial Hospital between
1949 and 1991. The variant histologic types are similar to squamous cell carcinoma and adenocarcinoma of the esophagus with respect to clinical presentation, method of diagnosis, and stage of disease at presentation. Most patients are in the seventh decade of life, male, and have a history of tobacco use, dysphagia, weight loss, and an advanced-stage esophageal malignancy at presentation. With the exception of small-cell carcinoma, treatment and overall survival of patients with the rare carcinomas are similar to those for squamous cell and adenocarcinoma of the esophagus. At Memorial Hospital a review of 258 patients who underwent resection for esophageal carcinoma between 1985 and 1991 was associated with a 27-month median overall survival for adenocarcinoma and a 22-month median overall survival for squamous cell carcinoma of the esophagus (unpublished data). These survivals are comparable to the 20.5-month survival for patients with resectable mucoepidermoid carcinoma of the esophagus. Outcome is most strongly influenced by extent of disease defined by TNM stage." Small-cell carcinoma appears to be a more aggressive variant of carcinoma manifested by diminished overall survival. Treatment is chemotherapy oriented for small-cell carcinoma, whereas the other tumors are most often treated by resection. The unusual variants appear to behave like squamous cell carcinoma and adenocarcinoma of the esophagus with respect to the propensity for both local and distant recurrence." The histogenesis of mucoepidermoid carcinoma of the esophagus is from the tubuloalveolar mucous glands of the submucosa.v'' The prevalence of the tumor is 0.4% in this series, which is similar to the prevalence in the report
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I I42
Table III. Perioperative mortality according to tumor characteristics and cause of death Patient age.sex 65, 52, 70, 75,
M M M M
58, F
Histologic type
Stage
Site
Operation date
Cause of death
Treatment
ME ME SC SC
III IV III IV
Middle Distal Distal Distal
1971 1979 1975 1986
Tracheopleural fistula Acute MI Pneumonia/sepsis Anastomotic leak/sepsis
AC
III
Middle
1986
Aspiration/sepsis
Thorocostomy tube Vasopressors Antibiotics/ventilator Esophageal diversion and drainage Antibiotics/ventilator
ME, Mucoepidermoid carcinoma; MI, myocardial infarction; SC, small-cell carcinoma; AC, adenoid cystic carcinoma.
of Suzuki and Nagayo! of 0.4% of 11,932 patients with malignant esophageal neoplasms. Twenty-two cases of mucoepidermoid carcinoma of the esophagus have been reported in the English literature. 5- 12 The results were pooled and analyzed for overall survival. Most patients were male (78%), the median age was 60 years, and presentation included dysphagia and weight loss. Primary treatment was esophagectomy (91%) or radiation therapy (9%). Of the 20 patients who underwent resection, 4 died perioperatively and the remaining patients had a median overall survival of 12 months (Fig. 2). The two patients treated with radiation therapy died within 7 months of diagnosis. Patients who had recurrences died of distant disease. This study demonstrated a longer duration of survival for patients who underwent esophagectomy (median disease-specific survival of 21 months). However, most patients had recurrences at distant sites and died. The difference in survival noted between this study and the small combined series probably reflects differences in patient selection for esophagectomy. The prevalence of small-cell carcinoma ranges from 0.02% to 2.4% of malignant esophageal tumors.P'" The cell of origin of small-cell carcinoma of the esophagus is from the argyrophilic cells of the epithelial basal layer. I 7 The tumors stain positive by Grimelius and neuron-specific enolase and demonstrate neurosecretory granules by electron microscopy. Grossly, most tumors are fungating lesions located in the distal two thirds of the esophagus. 16 Most patients are first seen with dysphagia and weight loss. Although tumors may stain for various hormones (adrenocorticotrophic hormone and calcitonin), detection of secreted hormones or clinical syndromes is rare. 17-21 A total of 124 cases of small-cell carcinoma of the esophagus have been previously reported in the English literature and are available for survival analysis. lO, 13, 15-44 The treatment for these patients included esophagectomy (46%), chemotherapy (14%), radiation (6%), chemotherapy and radiation (14%), esophagectomy and chemotherapy (5%), and no therapy (17%). Raw data from these patients were analyzed to generate survival curves by the Kaplan-Meier method.? and comparisons were determined by log-rank test.' The median
overall survival was 5 months. Figure 3 depicts the actuarial survival of the 107 patients who received therapy. Descending order of duration of overall survival was esophagectomy plus chemotherapy (n = 6; median survival, 28 months), chemotherapy and radiation (n = 36; median survival, 8 months), esophagectomy (n = 57; median survival, 5 months), radiation therapy (n = 8; median survival, 2.5 months), and no therapy (n = 17; median survival, I month). Patients died of distant disease. This collected experience shows results similar to ours. Small-cell carcinoma is a highly aggressive carcinoma with a propensity for distant metastases at presentation or shortly thereafter. Primary therapy is chemotherapy. However, results reported in the literature and findings from this study suggest a survival advantage for patients who undergo resection plus chemotherapy. Adenoid cystic carcinoma arises in the tubuloalveolar ducts of the mucus glands of the submucosa.v 45, 46 The prevalence of adenoid cystic carcinoma of the esophagus ranges from 0.07% to 0.8% of cancers of the esophagus. I , 46 The patient typically is first seen with dysphagia. The tumor is grossly fungating and infiltrating and most commonly located in the middle third of the esophagus.f Thirty-eight of 50 reported cases that involved the esophagus are available for analysis. I ,6,45-58 The male-tofemale ratio was 2.5, and the median age was 62 years (range, 36 to 83). Metastases developed in 50% of patients, the majority of which were widespread to liver, lung, and brain. Five of the 38 patients had widespread metastases on presentation and died within 6 months of diagnosis after no therapy or incomplete chemotherapy. Five patients with locoregional disease were treated with radiation therapy: three died of disease at I to 21 months and two are without evidence of disease at 8 and 16 months. Twenty-eight (74%) patients underwent esophagectomy with a perioperative mortality rate of 21%. A Kaplan-Meier curve/ was generated for the 22 patients who survived esophagectomy (Fig. 4). The median survival was 24 months, and the 3-year survival was 35%. These results are discouraging relative to those of adenoid cystic carcinoma of the salivary gland for which 5-year
The Journal of Thoracic and Cardiovascular Surgery Volume 108, Number 6
Lieberman et at.
1 14 3
Proportion Surviving
1<»-----------------------_ 0.9 0.8
0.7
Median-12 mos
0.6 0.5 0.4 0.3 0.2 0.1
OL------'--------'---------'-----'------------' 48 60 o 12 24 36
Time (rnos) Fig. 2.· Overall actuarial survival of 16 patients who survived resection for primary mucoepidermoid carcinoma of esophagus (5-year survival; 18%). (Modified with permission from Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsberg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).) Proportion Surviving 1tiiil-'?"-----'ii'--'V'-------------------------,
0.9 0.8
0.7
0.6 0.5 0.4 0.3 0.2 0.1
o L--------J;-----------'--~==~~----~-~ 24 36 o 12 Time (rnos) ---&-
Radiation Rx (n-S)
--+- Resection (n-57)
--£-
Chemotherapy (n-36)
--'i1-
Resect
+
Chemo (n-6)
Fig. 3. Overall actuarial survival of 107 patients with primary small-cell carcinoma of esophagus who received radiation therapy, esophagectomy, chemotherapy, or esophagectomy and chemotherapy. (Modified with permission from Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsberg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).)
survival was 69% in 264 patients who underwent resection.59 Carcinosarcoma is an uncommon tumor with features of carcinoma and sarcoma. The most recent findings concerning the histogenesis of this tumor are that the sarcomatous elements arise by spindle cell metaplasia of squamous cell carcinoma/" The prevalence of carcinosarcoma in large series of esophageal malignancies ranges from 0.3% to 2.4%.10,61-63 In a review of the English literature, 73 cases of primary carcinosarcoma of the
esophagus were available for analysis. 62-n The initial clinical presentation is similar to that of squamous cell carcinoma with dysphagia (80%) and weight loss (61%) predominating. The locations of the tumors were 13% upper, 59% middle, and 28% lower third of the esophagus. Forty-five patients were available for survival analysis. One patient was treated with radiation therapy and seven patients died in the early postoperative period. The overall survival of 34 patients who underwent esophagectomy for primary carcinosarcoma (excluding early post-
1 14 4
The Journal of Thoracic and Cardiovascular Surgery December 1994
Lieberman et al.
Proportion Surviving
1
"J,
0.9 0.8
t----t
0.7
N-22
0.6 0.5 0.4
0.3 0.2
Median-24 mos
0.1
o
o
12
24
36
60
48
Time (mos) Fig. 4. Overall actuarial survival of 22 patients who survived resection for primary adenoid cystic carcinoma of esophagus. (Modified with permissionfrom Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsberg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).)
Proportion Surviving 1< r ' & ' v - - - - - - - - - - - - - - - - - - - - - - - - - - - - ,
0.9
0.8 0.7
0.6 0.5
0.4
0.3
N-34
0.2 0.1
o o
L-
~
12
__L
__'___
24
36
_'__
48
_
60
Time Fig. 5. Overall actuarial survivalof 34 patients who survived resection for primary carcinosarcoma of esophagus (5-year survival, 55%). (Modified with permission from Burt M. Rare primary malignant tumors of the esophagus. In: Pearson GF, Deslauriers J, Ginsburg RJ, Hiebert CA, McKneally MF, Urschel HC, eds. Esophageal surgery. New York: Churchill Livingstone [In press).)
operative deaths) is illustrated in Fig. 5. The 5-year actuarial disease-specific survival for this group is 54%. Patients die of distant metastases to liver, brain, lung, and bone. Locoregional metastasis to lymph node is a less common event. However, a recent Japanese study tn = 20) reported a 5-year survival of 28% and lymph node involvement in 65% of patients who underwent esophagectomy and complete lymph node dissection."
Thus it remains unclear whether carcinosarcoma represents a more favorable histologic variant. On the basis of our experience and previously published data, we recommend esophagectomy for patients with locally confined mucoepidermoid, adenoid cystic, or carcinosarcoma of the esophagus. Treatment for smallcell carcinoma should include preoperative chemotherapy followed by esophagectomy for patients with
The Journal of Thoracic and Cardiovascular Surgery Volume 108, Number 6
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