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Pathologic evaluation of primary laryngeal anterior commissure carcinoma both in patients who have undergone open surgery as initial treatment and in those who have undergone salvage surgery after irradiation failure.

Abstract

Laryngeal anterior commissure (AC) cancer has been the subject of much controversy. Our study was aimed at pathologically evaluating the tendency of AC cancer to invade the thyroid cartilage and analyzing the role of thyroid cartilage invasion by tumor cells at the AC as an anatomic cause for irradiation failure. Our study included 36 patients with glottic cancer involving AC. Patients with recurrent or persistent disease after radiotherapy underwent salvage surgery. Surgical specimens from 22 patients who had open surgery, either as primary or salvage surgery, were available for pathologic examination to identify the presence of cartilage invasion. We found microscopic invasion of the thyroid cartilage in 40.9% of the studied tumors. Only 21.4% of patients who had open salvage surgery showed evidence of cartilage invasion at the AC. We concluded that laryngeal AC cancers are more likely to invade the cartilage, and that anatomic risk factors are not the main cause of irradiation failure.

Introduction

The anatomy of the anterior commissure (AC) and its impact as a tumor barrier have been the subjects of several investigations and are still subjects of controversy. (1-4) In addition to the mucosa, the AC includes the intermediate lamina of the thyroid cartilage and the AC tendon (also known as Broyles ligament) with its related structures. (1) The AC tendon represents a confluence of the vocal ligament, the thyroepiglottic ligament, the conus elasticus, and the internal perichondrium of the thyroid ala.

Some authors believe that the AC is a vulnerable location for tumor spread because it is here that the AC tendon inserts into the thyroid cartilage, and its involvement might induce susceptibility to tumor invasion. The lack of perichondrium or periosteum in the area of insertion of the AC tendon may allow invasion of tumors into the laryngeal skeleton. (1-5)

Because only a few millimeters separate the AC mucosa from the thyroid cartilage, a small tumor on the AC surface actually may penetrate the cartilage, thus changing the tumor staging. (6) However, some investigators believe that the AC tendon may act as a tumor barrier to glottic cancer, preventing invasion of the adjacent thyroid cartilage by cancer limited to the glottic level (Tla, Tlb). (3,7)

Early squamous cell carcinoma of the vocal folds has traditionally been treated with curative radiotherapy

with an excellent cure rate (85 to 95%) and preservation of voice quality. (8,9) However, glottic tumors that involve the AC have been viewed differently. Questions about whether AC involvement is an adverse prognostic factor, and whether the cause is anatomic or technical, have been the subjects of much research and still require further investigation.

Anatomically, the AC tendon penetrates the thyroid cartilage and causes dehiscence of the perichondrium at its site of insertion. This disruption might induce susceptibility to tumor invasion. (10,11) Technically, the reduced local control can be attributed to underdosage of radiation to the AC, as postulated by some investigators, owing to the type of energy used. (12,13) The AC is located near the air-tissue interface, and there is a greater risk of underdosage at that interface with the depth-dose characteristics of 4 MV or 6 MV using a linear accelerator than with those of cobalt-60.

The aims of the present study were (1) to evaluate the behavior of glottic cancer involving the AC with regard to its tendency to invade the cartilage and (2) to analyze the role of thyroid cartilage invasion by tumor cells at the AC as a possible anatomic cause for recurrent or persistent tumors after curative radiotherapy.

Patients and methods

Our study included 36 patients with glottic cancer involving the AC who were treated with curative intent between 1997 and 2007 at the Department of Otolaryngology, Second Hospital, Fujita Health University, School of Medicine, Nagoya, Japan. They represented 37.1% of the 97 patients treated for glottic cancer during the same period. The mean age of the patients was 65.25 years (range: 46 to 84 years).

Thirty-four patients were men, and only 2 were women. The patients were classified according to the 2002 International Union Against Cancer (UICC) larynx staging system, (14) by means of preoperative clinical records and computed tomography (CT) and endoscopic findings, as follows: 8 Tla (22.2%), 12 Tlb (33.3%), 7 T2 (19.4%), and 9 T3 (25%). Of the 36 patients, 24 were treated with radiotherapy as the primary treatment modality, and 12 were treated surgically (8 with open surgery and 4 with endoscopic C[O.sub.2] laser resection).

Radiotherapy was administered using the same technique for all patients. A linear accelerator with a beam energy of 4 MV photons was used. A mean dose of 66 Gy (range: 60 to 70 Gy) in 2-Gy fractions was delivered with one fraction per day, 5 days per week. After completion of the radiotherapy regimen, tumor response was evaluated by endoscopic examination and biopsy of any suspicious lesion. The mean follow-up period was 38.4 months (range: 18 to 84 months).

Recurrent or persistent tumors after radiotherapy were treated either with open salvage surgery (partial or total laryngectomy) or endoscopic C[O.sub.2] laser resection. Surgical specimens were available only from patients treated with open surgical techniques, either as the first line of treatment or as salvage therapy for persistent or recurrent tumors after radiotherapy.

During the microscopic evaluation, the greatest attention was given to those slices most representative of the tumor in relation to the thyroid cartilage.

Results

Twenty-two tumors from the patients who underwent open surgery, either initially (n = 8) or as salvage surgery after unsuccessful radiotherapy (n = 14), were examined. Microscopic invasion of the thyroid cartilage was detected in 9 of the 22 (40.9%) examined tumors (table). Of the 24 patients treated with radiotherapy, 9 (37.5%) had a complete response and 15 (62.5%) had persistent cancer or developed a local recurrence; 14 of 15 (93.3%) patients in the latter group underwent open surgery, and 1 patient (6.7%) underwent endoscopic C[O.sub.2] laser resection.

Microscopic invasion of the thyroid cartilage was detected in only 3 of the 14 (21.4%) examined tumors excised from patients who underwent open surgery after irradiation failure. All 3 cases showed indications of moderately differentiated squamous cell carcinoma, including basal cell proliferation, intermediate prickle cell hyperplasia with keratohyalin granules, and variable areas of keratin formation. Tumor edges appeared as round masses forming an expanding border; this border is sometimes referred as the tumor's "pushing border" suggesting that these tumors invade by pressure rather than by cell infiltration. A layer of multinucleated giant cells at the interface between the tumor and cartilage was noted in 2 cases (figure).

[FIGURE OMITTED]

All 3 tumors with thyroid cartilage microinvasion were staged as T2 lesions either before radiotherapy started or after showing evidence of recurrence or persistent disease.

Discussion

The special anatomic characteristics of the AC make this site even more difficult to stage than other parts of the larynx. Tumors originating in this area represent one of the greatest challenges for laryngeal cancer evaluation and treatment because the behavior of tumors in this region seems to be somewhat different from that of other glottic tumors. They deserve special consideration when treatment modalities are considered. The absence of internal perichondrium in the thyroid cartilage, in the region of insertion of the AC tendon, may account for the frequency with which tumors are found invading the cartilage at this point. (2,3)

In the present study, microinvasion of the thyroid cartilage was found in 9 of 22 (40.9%) examined tumors. Barbosa et al studied 52 patients with laryngeal cancer (stages T1 to T4) involving the AC and observed thyroid cartilage invasion in 42.3% of the examined tumors. (15) Rifai and Khattab performed a whole-organ section study of 30 excised larynges with AC carcinoma, and they confirmed the presence of cartilage invasion in all studied specimens. (16)

The prognostic significance of AC involvement in the local control of glottic cancer treated with radiotherapy has been controversial. Some investigators have failed to find a correlation between AC involvement and an increased local failure rate, (12,17) whereas others have found a significantly increased local failure rate. (11, 18)

In our study, we identified an increased local failure rate in patients with glottic cancer involving the AC and treated with radiotherapy using a 4-MV linear accelerator. We investigated 24 cases of patients with laryngeal cancer involving the AC who had been treated with radiotherapy and found that 15 (62.5%) of them developed local recurrence or had persistent cancer.

Maheshwar and Gaffney examined 14 patients treated with radiotherapy for T1 glottic cancer involving the AC; 8 (57%) of these patients developed recurrences. (19) These findings were supported by Shvero et al in a study of 64 patients, (20) Nozaki et al in a study of 14 patients, (21) and Jin et al in a study of 70 patients. (22)

The cause of radiotherapy failure, whether technical or anatomic, represents another subject of controversy among researchers. Chen et al reported that AC involvement is a significant factor for a poor prognosis in T1 glottic cancer treated with linear accelerator radiotherapy devices. (23) They found that 5-year local control rates for patients with and without AC involvement were 55 and 90%, respectively. Interestingly, these effects were seen only in patients treated with a linear accelerator unit and not in those treated with a cobalt-60 unit.

Other investigators have reported that AC involvement is a significant prognostic factor for patients treated with both cobalt-60 and linear accelerators and have suggested that the AC, through its specific anatomic features, may represent a weak point for tumor spread, regardless of the type of energy used. (11,24) However, most of the studies concluding that the anatomic features of the AC are the main cause of radiotherapy failure (11,20,24) lacked a microscopic examination of the AC region to detect histopathologic evidence supporting this concept, as was performed in our study. Interestingly, we found that microinvasion of the thyroid cartilage in the region of the AC was absent in approximately 79% of patients who underwent open surgery after failed radiotherapy. These results may represent pathologic evidence that anatomic risk factors are not the main cause of radiotherapy failure in these patients.

In conclusion, there has been much controversy about whether AC involvement in laryngeal glottic cancer is an adverse prognostic factor and whether the cause of irradiation failure is anatomic or technical. Our study identified an increased local failure rate in patients with glottic cancer involving the AC and treated with radiotherapy. However, we identified pathologic evidence suggesting that anatomic risk factors are not the main cause of radiotherapy failure in these patients, but that technical risk factors should also be considered when discussing this issue.

References

(1.) Broyles EN. The anterior commissure tendon. Ann Otol Rhinol Laryngol 1943;52:342-5.

(2.) Bagatella F, Bignardi L Behavior of cancer at the anterior commissure of the larynx. Laryngoscope 1983;93(3):353-6.

(3.) Kirchner JA, Carter D. Intralaryngeal barriers to the spread of cancer. Acta Otolaryngol 1987;103(5-6):503-13.

(4.) Rucci L, Gammarota L, Gallo O. Carcinoma of the anterior commissure of the larynx: II. Proposal of a new staging system. Ann Otol Rhinol Laryngol 1996;105(5):391-6.

(5.) Shvero J, Hadar T, Segal K, et al. T1 glottic carcinoma involving the anterior commissure. Eur J Surg Oncol 1994;20(5):557-60.

(6.) Krespi YP, Meltzer CJ. Laser surgery for vocal cord carcinoma involving the anterior commissure. Ann Otol Rhinol Laryngol 1989; 98(2):105-9.

(7.) Kirchner JA. Fifteenth Daniel C. Baker, Jr, memorial lecture. What have whole organ sections contributed to the treatment of laryngeal cancer? Ann Otol Rhinol Laryngol 1989;98(9):661-7.

(8.) Moose BD, Greven KM. Definitive radiation management for carcinoma of the glottic larynx. Otolaryngol Clin North Am 1997;30 (1):131-43.

(9.) Barthel SW, Esclamado RM. Primary radiation therapy for early glottic cancer. Otolaryngol Head Neck Surg 2001;124(1):35-9.

(10.) Rucci L, Gammarota L, Borghi Cirri MB. Carcinoma of the anterior commissure of the larynx: I. Embryological and anatomic considerations. Ann Otol Rhinol Laryngol 1996;105(4):303-8.

(11.) Marshak G, Brenner B, Shvero J, et al. Prognostic factors for local control of early glottic cancer. The Rabin Medical Center retrospective study on 207 patients. Int J Radiat Oncol Biol Phys 1999;43(5): 1009-13.

(12.) Sombeck MD, Kalbaugh KJ, Mendenhall WM, et al. Radiotherapy for early vocal cord cancer: A dosimetric analysis of 60CO versus 6 MV photons. Head Neck 1996;18(2):167-73.

(13.) Zohar Y, Rahima M, Shvili Y, et al. The controversial treatment of anterior commissure carcinoma of the larynx. Laryngoscope 1992; 102 (1):69 -72.

(14.) Sobin LH, Wittekind CH. UICC TNM Classification of Malignant Tumors. 6th ed. New York: John Wiley & Sons, Inc.; 2002:19-47.

(15.) Barbosa MM, Araujo VJ Jr., Boasquevisque E, et al. Anterior vocal commissure invasion in laryngeal carcinoma diagnosis. Laryngoscope 2005;115(4):724-30.

(16.) Rifai M, Khattab H. Anterior commissure carcinoma: I-histopathologic study. Am J Otolaryngol 2000;21(5):294-7.

(17.) Benninger MS, Gillen J, Thieme P, et al. Factors associated with recurrence and voice quality following radiation therapy for T1 and T2 glottic carcinomas. Laryngoscope 1994;104(3 Pt 1):294-8.

(18.) Le QT, Fu KK, Kroll 8, et al. Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma. Int J Radiat Oncol Biol Phys 1997;39(1):115-26.

(19.) Maheshwar AA, Gaffney CC. Radiotherapy for T1 glottic carcinoma: Impact of anterior commissure involvement. J Laryngol Otol 2001; 115(4):298-301.

(20.) Shvero J, Hadder T, Segal K, et al. Early glottic carcinoma involving the anterior commissure. Clin Otlaryngol Allied Sci 1994;19(2): 105-8.

(21.) Nozaki M, Furuta M, Murakami Y, et al. Radiation therapy for T1 glottic cancer: Involvement of the anterior commissure. Anticancer Res 2000;20(2B): 1121-4.

(22.) Jin J, Liao Z, Gao L, et al. Analysis of prognostic factors for T(1) N(0)M(0) glottic cancer treated with definitive radiotherapy alone: Experience of the cancer hospital of Peking Union Medical College and the Chinese Academy Of Medical Sciences. Int J Radiat Oncol Biol Phys 2002;54(2):471-8.

(23.) Chen MF, Chang JT, Tsang NM, et al. Radiotherapy of early-stage glottic cancer: Analysis of factors affecting prognosis. Ann Otol Rhinol Laryngol 2003;112(10):904-11.

(24.) Zouhair A, Azria D, Coucke P, et al. Decreased local control following radiation therapy al one in early- stage glottic carcinoma with anterior commissure extension. Strahlenther Onkol 2004;180(2):84-90.

From the Department of Otolaryngology, Second Hospital, Fujita Health University, School of Medicine (Dr. Ahmed, Dr. Suzuki, Dr. Kato, Dr. Fujisawa, and Dr. Nishimura) and the Department of Pathology, Daidou Hospital (Dr. Horibe), Nagoya, Japan.

Corresponding author: Kenji Suzuki, MD, PhD, Department of Otolaryngology, Second Hospital, Fujita Health University, School of Medicine, 3-6-10, Otobashi, Nakagawa Ku, Nagoya, Japan 454-8509. Email: ken-suzu@fujita-hu.ac.jp
Table. Number and percentage of thyroid cartilage
invasions for each primary glottic tumor stage (T).

Stage    Studied   Cases with
          cases     invasion

            n        n  (%)
T1a         6        0 (0)
T1b         4        1 (25)
T2          3        2 (66.6)
T3          9        6 (66.6)
Total      22        9 (40.9)
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Title Annotation:ORIGINAL ARTICLE
Author:Ahmed, Wael A.; Suzuki, Kenji; Horibe, Yoshimune; Kato, Ichiro; Fujisawa, Toshiyuki; Nishimura, Yoic
Publication:Ear, Nose and Throat Journal
Article Type:Report
Geographic Code:9JAPA
Date:May 1, 2011
Words:2544
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