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Ann Thorac Surg 2004;78:1889-1897
© 2004 The Society of Thoracic Surgeons
a Division of Thoracic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
b Center for Clinical Effectiveness in Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, USA
c Policy Analysis Inc, Brookline, Massachusetts, USA
Accepted for publication May 20, 2004.
* Address reprint requests to Dr Gaissert, Division of Thoracic Surgery, Massachusetts General Hospital, Blake 1570, 55 Fruit St, Boston, MA 02114, USA
hgaissert{at}partners.org
Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
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Abstract |
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METHODS: We conducted a retrospective study of patients diagnosed with primary adenoid cystic carcinoma (ACC) or squamous cell carcinoma (SCC) of the trachea between 1962 and 2002. Laryngotracheal, tracheal, or carinal resection was performed when distant metastasis and invasion of adjacent mediastinal structures were absent and tumor length permitted. Radiotherapy was administered after operation (54 Gy), except in superficial tumors, or as palliation (60 Gy).
RESULTS: Of 270 patients with ACC or SCC (135 each), 191 (71%) were resected. Seventy-nine were not resected due to tumor length (67%), regional extent (24%), distant metastasis (7%), or other reasons (2%). Overall operative mortality was 7.3% (14/191) and improved each decade from 21% to 3%. Tumor in airway margins was present in 40% (17/191) of resected patients (ACC 59% versus SCC 18%) and lymph node metastasis in 19.4% (37/191). Overall 5- and 10-year survival in resected ACC was 52% and 29% (unresectable 33% and 10%) and in resected SCC 39% and 18% (unresectable 7.3% and 4.9%). Multivariate analysis of long-term survival found statistically significant associations with complete resection (p < 0.05), negative airway margins (p < 0.05), and adenoid cystic histology (p < 0.001), but not with tumor length, lymph node status, or type of resection.
CONCLUSIONS: Locoregional, not distant, disease determines resectability in primary tracheal carcinoma. Resection of trachea or carina is associated with long-term survival superior to palliative therapy, particularly for patients with complete resection, negative airway margins, and ACC.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Long-term survival after surgical resection of malignant tracheal tumors has been previously demonstrated [1–4]. The benefit of surgical therapy is less clear when resection is incomplete or lymph node metastasis present. In a preliminary analysis of tracheal squamous cell carcinoma (SCC), Grillo and Mathisen [5] showed a negative impact on survival when tracheal margins or lymph nodes were involved. For adenoid cystic carcinoma (ACC), a French cooperative study [6] demonstrated higher survival after complete resection, whereas Maziak and colleagues [7] did not find a significant difference in survival between complete and incomplete resection. A study of the two most common primary tracheal tumors, ACC and SCC, was conducted to examine presentation and resection rates, to further elucidate factors predictive of long-term survival, and to observe the role of incomplete resection and lymph node metastasis.
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Patients and Methods |
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Determination of Resectability
Patients underwent an assessment of locoregional and distant metastatic disease before resection. Radiographic evaluation included conventional tomography of trachea and carina [8] and computed tomography once available [9]. Every patient underwent bronchoscopy. The pathologic diagnosis was made from bronchoscopic biopsies or the resected specimen. Tracheal resection was considered only when complete resection seemed feasible. Microscopic involvement of airway margins was accepted if the airway was normal on gross inspection and no further length of airway could be resected. Resection was not performed when the procedure would have resulted in grossly positive peritracheal margins. A tumor was also considered unresectable when metastatic disease was present, the length of involved airway at bronchoscopy was judged to preclude safe reconstruction, or when invasion of certain adjacent organs was found during operative exploration. Esophageal invasion was resected in some patients.
Types of Resection
Resections were grouped by anatomic region and extent. For standard tracheal resection, a sleeve of trachea was removed with end-to-end reconstruction. When tracheal resection was combined with laryngectomy, cervical or mediastinal end-tracheostomy was required. For laryngotracheal resection, the tumor was removed with a portion of infraglottic larynx while preserving at least one recurrent laryngeal nerve not involved with tumor. Reconstruction was achieved by shaping the remaining trachea to conform to the laryngeal defect. Carinal resection was performed with or without concomitant lung resection. Carcinomas involving the carina by extension from the lung or a mainstem bronchus were excluded from analysis.
Systematic lymph node dissection was assumed to interfere with the tracheal blood supply and was therefore not performed. Regional lymph nodes were often not included in the specimen if not grossly enlarged. Absence of tumor at the airway margins was confirmed by frozen section unless the limits of resection had been reached and no additional trachea could be removed. The resection was judged to be complete when airway margins were found to be disease free and no statement in the operative note indicated that the resection was incomplete.
Tumor Data
Tumor dimension in the long axis of the airway, depth of invasion, and the presence of tumor at airway or radial margins were recorded in resected patients from a review of pathology reports. Positive airway margins indicated true residual, most often microscopic, tumor. In contrast, the radial margins were interpreted as positive when tumor was seen within 1 mm of the margin, usually indicating that only a thin layer of connective tissue covered the outside of the tumor. Tumor involvement of excised lymph nodes was noted.
Adjuvant and Primary Radiotherapy
Adjuvant postoperative radiotherapy was introduced during the second decade of this experience for close or tumor-bearing margins. After bronchoscopic assessment of anastomotic healing, a recommended dose of 54 Gy was administered 6 weeks after resection. Primary radiotherapy with 60 Gy was recommended for patients who had unresectable tumors, but could not be confirmed in all patients. Most patients received treatment outside MGH; a report from our hospital [10] found a median postoperative dose of 60 Gy.
Follow-Up
Patients and their physicians were contacted for follow-up information. The social security death index was searched. Patients were determined to have died if name, date of birth, and social security number matched. Follow-up information on treatment and tumor status in patients who did not undergo resection was often limited to the date of death.
Statistical Analysis
Patient averages for dichotomous and continuous variables were calculated overall and for tumor type (ACC and SCC). Where appropriate, statistically significant differences were between ACC and SCC were tested using the 
2 statistic (dichotomous variables) and the t-statistic (continuous variables). Finally, to better understand factors associated with long-term survival, we calculated univariate logistic analyses, multivariate logistic analyses, and survival analyses. The multivariate analyses predicted the likelihood of survival at 5 and 10 years based on clinical relevant factors (for tumor type, tumor length, type of resection, age, completeness of resection, positive lymph nodes, smoking status, and airway margin). The survival analysis depicted predicted survival based on patients with complete follow-up. All analyses were calculated using SAS version 8.0 (SAS Institute, Carey, NC).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Length and depth of resected tumors and status of resection margins are listed in Table 5. Adenoid cystic carcinomas were longer and extended more often into peritracheal soft tissues or to adjacent organs, most commonly the esophageal muscle coat. Tumor was therefore more often present at or close to the radial resection margin, and tracheal margins frequently contained microscopic tumor. Fifty-nine percent of patients with ACC had positive airway margins, in contrast to only 18% with SCC.
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Long-Term Follow-Up
Follow-up of survival was complete in 88.5% (239/270) of patients. The overall survival for all patients with primary tracheal carcinoma was 84% at 1 year, 45% at 5 years, and 25% at 10 years. Mean survival time was 38 months with resected SCC, 8.8 months with unresectable SCC, 69 months with resected ACC, and 41 months with unresectable ACC. Figure 1 depicts the survival by tumor type and resection status. At 5 years, 39.1% of patients with resected and 7.3% of patients with unresectable SCC survived. Five-year survival was 52.4% for resected and 33.3% for unresectable ACC. A comparison of survival after laryngotracheal, tracheal, and carinal resections is shown in Figure 2. Despite higher hospital mortality after carinal resection, differences in long-term survival between these types of resection were not significant.
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The logistic multivariate analysis of resected patients (Table 7) identified ACC, complete resection, and negative resection margins to be associated with 5-year survival and ACC, complete resection, and age to be associated with 10-year survival. Sensitivity analyses showed that either negative pathologic airway margins or complete resection as determined by the surgeon were associated with improved survival when run in separate models.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The sum of these observations suggests that most patients with tracheal cancer, in contrast to peripheral lung cancer, have limited disease when symptoms occur and are therefore good candidates for surgical therapy. Nonspecific symptoms, however, delay diagnosis and this delay may affect therapy as suggested by the difference in symptom duration between resected and unresectable patients.
We found that complete resection in ACC and SCC was associated with improved survival. A retrospective French multicenter study of 208 patients had also demonstrated the value of complete resection in ACC [6], but not so a study describing the experience with 38 patients at the University of Toronto [7]. The French report did not find a decrease of survival for patients with positive lymph nodes, which we observed in SCC. However, we did not find lymph node involvement predictive of survival in the multivariate analysis. These seemingly conflicting data were based on small numbers of lymph node-positive patients, and the multivariate analysis may have attributed any effect on outcome to squamous histology. The multivariate analysis did not establish other variables of disease extent as predictors of survival in either tumor, such as tumor depth or tumor length. These findings indicate the problems in characterizing basic oncologic relationships in primary tracheal carcinoma due to its low incidence and suggest a current lack of data to formulate a precise staging system.
Current staging methods have limited accuracy in defining the locoregional extent of disease. Computed tomography does not predict mediastinal organ involvement and underestimates the longitudinal reach of tumor in the airway [9]. Endoscopy supplemented by mucosal biopsies provides at present the best assessment of luminal tumor length. Although endoluminal ultrasound may distinguish reliably between compression and infiltration of the trachea by an extrinsic tumor [12], detection of submucosal infiltration, by far the most common cause of positive tracheal resection margins, has not been reported. Despite the shortcomings of present locoregional staging, only 17 of 208 patients (8.2%) underwent operative exploration without resection.
A comparison of SCC and ACC of the trachea highlights their commonalities and distinctions. Both tumors were referred with equal frequency and together constituted more than 95% of primary tracheal carcinomas. In contrast, epidemiologic studies, without review of pathology or radiographs, consistently find other bronchogenic carcinomas in 15% to 20% and adenoid cystic tumors in fewer than 15% of patients [11, 13]. A difference in growth rate may introduce lead-time bias but offers no satisfactory explanation for this disparity. Both tumors have high resection rates and share locoregional disease as the most common contraindication to resection. Effects of smoking, a higher age at presentation, and growth rates combine so that 43% of patients with ACC but only 10% of patients with SCC survive beyond 5 years. We did not determine whether incomplete resection is of curative or merely palliative value; the number of patients was too small. Although usually discovered when already committed to resection and thus of limited usefulness in determining resectability, we assume that incomplete resection due to positive tracheal margins continues to be justified in selected patients with ACC in the hands of experienced surgeons. The operative risk is low, a small although statistically not significant survival benefit is observed, and it is our impression that death occurs from metastatic disease rather than airway obstruction. Because locoregional tumor is the most important determinant of resectability and current resection methods rely on primary reconstruction with trachea, any further increase of the resection rate will depend on the development of a safe tracheal replacement.
Discussion
DR DONNA E. MAZIAK (Ottawa, Ontario, Canada): I would like to commend you on this landmark report in which you have presented the largest series and the longest follow-up in this relatively rare disease.
I have a few questions. First, looking at the lymph node status, you reported, and maybe I misunderstood, that patients with adenoid cystic who were lymph-node-negative did worse in terms of survival than people who were lymph-node-positive. Did you find most of your lymph nodes that were positive were more from direct extension rather than from a separate site away from the tumor? And did you look at perineural spread in patients with adenoid cystic carcinoma and the effect on survival? Quite often perineural spread is more common than lymphatic.
With regard to your cut-off for length of tumor that was resected, I think the longest was 3.5 cm. Sometimes longer resections are possible, and in our series with Dr Pearson we resected even up to 8 cm. I was wondering if you did no resections longer than 3.5 cm by choice or if that length was the standard cut-off at your institution. Also, did you notice if any patients who received radiation went from being unresectable to resectable? With regard to radiation, only 70% of your patients received postoperative radiation. With your findings and your conclusions, do you think now that most likely everyone should get radiation postoperatively?
Again, I would like to thank you for your report and for your presentation of these patients.
DR GAISSERT: Doctor Maziak, thank you very much for your questions.
With regard to the apparent better survival for lymph-node-positive patients in adenoid cystic carcinoma, there were so few patients and they did not have an early decline in their survival as did the lymph-node-negative patients, so we suspect that this particular selection of patients underwent resection at a later time after an initial high mortality. I doubt that this survival difference can be attributed to lymph node disease.
It was our impression that most lymph nodes were not involved by direct extension but that they had tumor deposits by lymphatic spread. We did not examine the specific item of perineural spread in a separate manner.
We reported tumor length as a mean with standard deviation. Some patients had resections of up to 7 or 8 cm, but most of those underwent a laryngectomy and a mediastinal tracheostomy at the same time.
Finally, with regard to preoperative radiation, we accepted patients with preoperative radiation and examined whether they were candidates and then treated them differently from other patients in that we wrapped the anastomosis in vascularized tissue, such as omentum, but because of our own bias, we did not treat patients with preoperative radiotherapy.
DR ROBERT J. KORST (New York, NY): I enjoyed the presentation immensely.
What are the patients dying of? Specifically what are the recurrence patterns? Are you seeing a lot of local recurrence? Are there distant failures?
DR GAISSERT: I would like to show the next slide, if you will allow me. [Shows slide.]
To answer your question, Dr Korst, this slide shows the vital status and the recurrence pattern as best as we can determine, and this is the weakness of a retrospective study that looks at a long time period during which patients have been referred mostly from other regions and we sometimes have difficulty getting the data. You see from this slide that a fairly large number of patients died with an unknown status or had social security numbers that were not deactivated and they were lost to follow-up. Most of the 23% of patients who died of disease had distant metastatic disease; in the case of adenoid cystic carcinoma, most metastases were to lung, bone, and brain. Regarding the frequency of local recurrence, we had 18 patients with squamous cell carcinoma who had a local recurrence compared with 5 patients with adenoid cystic carcinoma. We did not find, by the way, a correlation with postoperative radiotherapy, so we could not identify an effect, positive or negative, of postoperative radiotherapy.
DR GIUSEPPE CARDILLO (Rome, Italy): Some endoscopists perform an endoscopic resection of the tumor before sending patients to the surgeon. We believe that this procedure is dangerous. What is your opinion about an endoscopic resection before definitive surgery?
DR GAISSERT: We have performed endoscopic resection in some instances in which we wanted to delay treatment because the patient was still on steroids. At that time we did the endoscopic resection with bronchoscopic methods and without the use of laser. We have a great concern about using laser for endoscopic resection because the laser may extend the damage and thus convert a potentially resectable lesion to an unresectable lesion. So we discourage the use of laser.
DR JOSEPH B. SHRAGER (Philadelphia, PA): This is a beautiful study, and, as everyone knows, it could not come from anywhere but Massachusetts General Hospital given the volume of patients undergoing tracheal surgery up there.
For the adenoid cystic group, something that really struck me is that the survival curves for those who had a positive airway margin and the nonsurgical cases were basically overlapping. Apparently operation confers no survival benefit on patients who have a positive airway margin, thus perhaps you could opt to not operate on those patients. So the question I have—and I'm not aware of any data on the issue so maybe you can shed light on this—is whether there are any data that tell you the mean microscopic extension of disease beyond the gross tumor. If you knew what the extension beyond the gross disease is likely to be, then you could choose which patients might be reasonably approached surgically and which would be better served by radiation alone.
DR GAISSERT: Thank you, Dr Shrager. That is an excellent question and one that is important to us: Can you predict whether a resection is going to be complete or incomplete on the airway? We do not think you can. You may say that a length of tumor likely will result in a positive airway margin, but you cannot predict with certainty whether eventually that is going to be the case. And you find out when all the bridges are burned and you are essentially committed to reconstruction.
The next question is whether an incomplete resection has a palliative value. I have not shown this here and I do not think that we have all the data to show that. Nevertheless, with an operative mortality of 3%, I think one can make a case for palliative resection, even though only a small group of patients who undergo an incomplete resection reach the 15-year mark. Some do, but we do not know who does and who does not.
DR SHRAGER: I believe I see the back of Dr Grillo's head a few rows in front of me. If Dr Grillo is here, I would love to hear him comment.
DR GAISSERT: Doctor Grillo, would you like to comment on this question?
DR HERMES C. GRILLO (Boston, MA): I do not know that I have that much to add to the excellent presentation Dr Gaissert made, but I think this study does show some of the problems of the rarity of the disease. It has taken 40 years to make this accumulation, and, as you point out, there are problems inherent in follow-up, especially when the patients have come from basically all over the world, and it is difficult to extract some of the refined questions that have been asked from these data or to set up anything prospectively that is ever going to answer some of those questions. So I regret that we cannot answer them all.
Insofar as the problem of whether it is worth doing a resection if there is a positive margin, first of all, as Dr Gaissert pointed out, you have no option. In that sense you have reached that point, and at that point you have to stop. Early on we did not stop, and you can see what the mortality was. However, we do know that death from airway obstruction is a wretched and miserable death, and most of these people, when they did die of their disease, died from distant metastases, lung in particular, along with some bone and some other, which is not pleasant but is different; this has been actually one of the rationales for why we have gone ahead. In, say, thyroid cancer invading the airway, even in the presence of slow-moving pulmonary metastases, as are some of these adenoid cystic pulmonary metastases, we have considered it worthwhile to go ahead and remove the airway obstruction for the patient's benefit.
DR RICHARD FEINS (Rochester, NY): Thank you very much, Dr Gaissert and Dr Grillo. We are very fortunate in general thoracic surgery this year to have the publication of Dr Grillo's book on tracheal surgery and I am sure it will stand as the sentinel work in that area. So for those of you who are interested in great books, that book, as a lifelong work, has now been published. Thank you, Dr Grillo, for that.
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