PANENDOSCOPY IN HEAD
AND NECK CANCER
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds
DATE: January 16, 1996
RESIDENT PHYSICIAN: James Grant, M.D.
FACULTY: Christopher H. Rassekh, M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.
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The head and neck cancer patient must be evaluated in a systematic and thorough manner. In the initial assessment, usually in an office setting, of the patient with suspected head and neck cancer, a detailed history is taken with special attention given to exposure or use of tobacco and / or alcohol. A quantitative history is important. Symptoms or signs that should signal the physician to search for malignancy, especially in those with long history of tobacco or alcohol use, includes prolonged sore throat, dysphagia, odynophagia. change in denture fit, or trismus. In addition, hoarseness, dysphonia, respiratory problems (i.e. stridor), hemoptysis, chronic cough, nasal stuffiness or obstruction, neurological complaints (i.e. facial numbness, motor weakness), otalgia and neck swelling or presence of a mass are also important. The signs and symptoms remain varied, if present at all in some patients, requiring the physician to maintain a high index of suspicion for cancer. The otorhinological examination must be thorough, with systematic evaluation of the nose, ears, oral cavity / oral pharynx, and neck.
While the oral cavity and oral pharynx may be inspected directly, visualizing the nasopharynx, hypopharynx, and larynx requires the use of indirect mirror laryngoscopy and/or flexible fiberoptic endoscopy or rigid telescope (nasal cavity). Radiographic studies may be indicated such as CT, MRI, panorex, as well as routine chest x-ray (searching for evidence of metastatic disease an a second primary) and possibly, depending on if the patient is symptomatic and / or the institutions policy on routine screening studies, a upper gastrointestinal contrast study is obtained. Histological diagnosis is, of course, paramount with certain lesions being accessible for simple office biopsy (fine needle aspiration, punch biopsy); whereas, other lesions may require obtaining a tissue sample under general anesthesia. The role of using panendoscopy as routine aspect in evaluating the head and neck cancer patient has remained controversial, especially regarding whether radiological screening studies may supplant the endoscopic procedure. This will be discussed further.
Panendoscopy encompasses the use of direct laryngoscopy, bronchoscopy, and esophagoscopy in the evaluation of the head and neck cancer patient. The basic goals of the endoscopic procedures is to map the extent of the already documented lesion for staging purposes / efficacious treatment planning, to search for a recurrence in an already treated patient, to obtain a tissue sample of an otherwise in accessible lesion, to examine for an unknown primary in a patient with documented cervical metastasis, and to search for a other malignant lesions in the aerodigestive tract (synchronous primaries). The concept of searching for multiple primaries is important and plays an integral role in the use of routine panendoscopy. Historically, in 1860 Bilroth presented the first documented case of multiple primary carcinomas, which later Warren and Gates, in 1932, describe a 3.7% incidence of multiple neoplasms in a study based on 1,078 autopsies. The criteria for defining a second primary malignancy were established by Warren and Gates and include the following characteristics : (1) the tumor must be clearly malignant by histological examination, (2) each tumor must be geographically distinct and not connected by submucosal or intraepithelial changes, and (3) the possibility of the second tumor representing a metastasis must be excluded. This criteria has been the classical premise applied in the literature as labelling a tumor as a second primary.
Slaughter, et al. reviewed cases of patients with lip, oral cavity, and pharyngeal carcinoma in an effort to explain the increased incidence of multiple primary malignancies in the head and neck cancer patient. By studying the tumors of these patients both macroscopically and microscopically, he found that most oral cavity cancers have a greater linear extent along the mucosa than actual depth of invasion and that the epithelium beyond the margins of the malignancy demonstrated a variety of microscopic changes such as hyperplasia, hyperkeratinization, and round cell infiltration. In addition, he found that in every instance in which a tumor was greater than one centimeter in diameter, a separate focus of in situ cancer was noted. Based on his findings, Slaughter presented the concept of "field cancerization" to elucidate the presence of multiple primary lesions. According to this concept, the protracted and intense use of certain agents (i.e. tobacco, alcohol), produces a regional surface contact carcinogenic effect in which a preconditioned epithelium is activated over a widespread area allowing multiple groups of cells to undergo a process of irreversible transformation to cancer.
Most medical centers treating head and neck cancer patients perform an endoscopic procedure on the patient prior to making a treatment plan. At the very least, it is performed to examine the true extent of the tumor or to obtain a biopsy in an inaccessible region. The use of triple endoscopy, however, in examining for the presence of multiple primary tumors is what remains controversial. Several centers believe that a screening radiographic study is sufficient to rule out the presence of a lesion, especially in the asymptomatic patient. Especially in today's healthcare system of cost containment, the price of panendoscopy is not justified, according to certain investigators, if the easier, less costly, radiographic studies are negative. On the other hand, several investigators argue that there are several false negative radiographic studies and that the documented high incidence of multiple primary malignancies in the head and neck cancer patient justifies panendoscopy. Certain studies are presented for review.
In a study published in 1979, D.P Vrabece reported an 11.5% rate of multiple primary cancers out of 1518 patients examined. Additionally, the frequency of the site of second malignancies was studied in relationship to the site of the index tumor. His results showed that when the index tumor was in the oral cavity the most common location of the synchronous primary was also on the oral cavity, followed by the lung. In contrast, when the index tumor was laryngeal or pharyngeal, the most common site for a second primary tumor was the lung, followed by the esophagus. The paper also addressed the high incidence of false negative finding on barium swallow (64%) when an actual lesion was detected on esophagoscopy; furthermore, chest x-ray false negatives approached 56% as lesions were found on bronchoscopic examination. Based on these results, panendoscopy is a justified as a routine preoperative evaluation in this patient population.
In study published by Mc Guirt, et al in 1982, he affirmed the use of panendoscopy in searching for a second primary lesion. With a patient population of 100, he found a 16% incidence rate of second primary lesions. In detail, 8/16 had an esophageal second primary, 5/16 had a second primary in the head and neck region, while 3/16 had a second primary located in the lung. Of interest, Mc Guirt contends that a significant percentage of these lesions were found because routine panendoscopy was performed, without which they would not have been properly identified. For instance, in those with an esophageal lesion (n=8), four of the eight were asymptomatic and were not evaluated with an esophogram (symptom directed radiological studies); hence, diagnosis was made at the time of esophagoscopy. In addition, of the lung second primaries (n=3), all were asymptomatic with 1/3 of having a normal chest x-ray. Although most of the patients having a second primary in the head and neck region (n=5) were symptomatic, one out of the five had a silent lesion detected only on direct laryngoscopy. In all, Mc Guirt states that 6/16 had clinically silent tumors based on the premise that they would not have been detected as early by clinical examination or symptom only directed studies. According to his results, panendoscopy is justified. Of note, Mc Guirt also attempted to find an association between multiple primaries and patient or tumor characteristics. He did not find a correlation between the incidence of a second primary and patient age, sec, anatomical location, or stage of the index tumor.
A multi-institutional prospective study by Leipzig, et al. also argues that panendoscopy should be a routine step in properly evaluating the head and neck cancer patient. From their data, they give an incidence of 8.9% second primaries, of which 3.3% were found in the lung, 1.8% found in the esophagus, and 3.6% in the head and neck region. They give a surprisingly high percentage (58%) of tumors that were detected solely by panendoscopy (i.e. negative symptoms, false negative radiological screening study). To elaborate, in those with second primaries located in the lung, 6 out of 13 patients had normal chest x-rays with findings of malignancy on bronchoscopic examination. In contrast, however, 2 of the 13 patients who were eventually confirmed to have a lung second primary had abnormal chest x-rays without confirmation on bronchoscopy. In reference to the esophageal second primaries, 7 malignant lesions were found in all, with 3/7 having abnormal esophagram, 1/7 having a normal esophogram, and 3/7 not undergoing a study because of the lack of symptoms. In the patients with a second primary in the head and neck region, only 3/14 were able to be detected on office clinical examination prior to panendoscopy. Of the fourteen (14) lesions found, eight were in the hypopharynx. This area (especially the pyriform sinus) is especially difficult to examine appropriately and often requires direct laryngoscopy for completeness. The authors contend that panendoscopy, in addition to a routine screening chest x-ray, is invaluable in evaluating the head and neck cancer patient, especially in light of detecting several silent lesions that were otherwise not detected radiographically or by clinical examination.
In contrast to the above studies, Maisel, et al. performed a retrospective study with results leading the authors to argue that direct laryngoscopy and esophagoscopy are warranted routine procedures, but bronchoscopy should not be included. In their study, they reviewed 449 patient's chart with documented squamous cell carcinoma of the head and neck and found an incidence of 36 simultaneous primary tumors, or an 8% incidence. More specifically, of the 36 second primaries, 17/36 were found in the lung, 4/36 were found in the esophagus, and 15/36 were found in the head and neck region. The authors state that the role of direct laryngoscopy under general anesthesia recommended as part of the initial evaluation for locating the head and neck second primary as only 7/15 were found prior on clinical, office setting examination. The remaining 8 lesions were not documented until direct laryngoscopy was performed. In addition, the inferior extent of the index tumor was able to be identified. Regarding those patients with an esophageal lesion (n=4), only two of the patients had an abnormal contrast radiographic study, thus requiring esophagoscopy for identification of the lesions. With respect to bronchoscopy, the authors's state it should not be a routine aspect of panendoscopy based on their findings. Of the patients with a lung second primary (n=17), all of them had an abnormal chest x-ray. They state that despite the abnormal chest x-ray bronchoscopy could not detect the abnormal lesions in five of the seventeen patients. Thoracotomy, mediastinoscopy, or autopsy was required for tissue diagnosis of this patient population. The authors state that there were no patients with a normal chest x-ray with findings of a second primary on bronchoscopy. Thus, the chest x-ray as a screening tool had a 0% false negative rate, at least for their study. Given this result, they argue that routine bronchoscopy is not indicated, but should be reserved for those patients in which there is a firm clinical suspicion, i.e. abnormal chest x-ray. In summary, Maisel, et al, recommends a routine chest x-ray, direct laryngoscopy with bimanual palpation of the mucosa, and esophagoscopy for the evaluation of the head and neck cancer patient.
In a more recent paper by Benninger, et al. the use of symptom directed endoscopy versus routine panendoscopy was examined. In their research design, 100 head and neck cancer patients underwent an evaluation which included a chest x-ray, barium esophagram, direct laryngoscopy, esophagoscopy, and bronchoscopy with bronchial washings. An incidence of 7% was found for multiple primary malignancies, of which six were found in the head and neck region while one was found in the esophagus. Three esophageal lesions (two primay, one second primary) were found on esophagoscopy of which two had an abnormal esophogram, while only one had a normal esophagram. All of the patients with the finding of an esophageal malignancy were symptomatic, i.e. complaining of dysphagia / odynophagia. In contrast, they stated there were no asymptomatic patients with abnormal findings on esophagoscopy. Per their study, they did not find any patients with a second primary contained in the lung, although two patients had evidence of metastatic disease. There were 15/100 abnormal chest x-rays, but after appropriate examination by bronchoscopy, no malignancy was identified. The author asserts that the yield of bronchoscopy in the absence of symptoms (hemoptysis, chronic cough, etc.) or an abnormal chest x-ray is low and should not be routinely used. He does make an exception for the large laryngeal tumor, stating bronchoscopy should be used. Additionally, he asserts that esophagoscopy is indicated only in those patients with symptoms of dysphagia and/or odynophagia, with a barium esophogram not needed if esophagoscopy is used in a symptom directed manner. Direct pharyngolaryngoscopy is essential in adequately assessing the patient and should be used routinely. In addition, a routine chest x- ray is indicated. Based on a symptom directed endoscopy approach, the total cost in these 100 patients would have been reduced by 67%.
In one of the largest studies to date, Haughey, et al. published a large meta-analysis study of second primaries in head and neck cancer patients from 24 previously issued studies, as well as their own retrospective review of 5.246 patients from Washington University. Based on this study, he notes that there is an overall second malignancy prevalence of 14.2% in this specific patient population. In detail, the study notes that 47% of the primaries are located in the head and neck, in contrast to 30% at other distant sites, 20% in the lungs, and only 3% in the esophagus. Additionally, the study explored the site relationship of the second malignancy to the index tumor, as Vrabec did in 1979. Head and neck second primary lesions were more likely to have a lesion in the oropharynx (67%) and least likely to have a laryngeal lesion (30%). With those having a lung second primary, however, the index tumor was likely t be laryngeal (27%) and least likely to have an oropharyngeal (11%) index tumor. No definite conclusions were drawn regarding esophageal second primaries based on their studies small incidence (5%). Of special note, oral cavity tumors had the largest incidence of secondary primary tumors. The author's were impressed with the high overall incidence of multiple primary malignancies in the head and neck cancer patient and state that prospective panendoscopy studies have a 2.5 times greater yield than the retrospective studies in which panendoscopy was not used routinely.
Finally, in an excellent review article by Levine, et al. a component of the paper discussed the comparable diagnostic accuracies between radiological studies and endoscopy procedures in detecting the second primary lesions. Based on the several studies that the were reviewed in this article, they found that rates of false negatives on the chest x-ray ranged from 0% (Maisel, et al) to 56% (Vrabec). The reason for false negatives is related to limitations of the chest x-ray, especially with small lesions. A bronchial malignancy must be greater than one centimeter in diameter for it to be detected on a chest x-ray. More specifically, if a neoplasm originates in the mainstem bronchus or within the mediastinal or hilar shadows, it may exceed greater than two centimeters before it may be detected by chest x-ray. Regarding the use of barium esophagrams versus esophagoscopy in detecting the digestive tract malignancies, there were several article that reported high rates of false negatives by radiographic studies (i.e. Grossman--75%, Vrabec--64%,, Shapshay--56%). In light of the false negative findings per radiographic screening studies in a population with a documented high incidence of second primaries, the authors concludes that panendoscopy is advocated as an effective screening tool as well as essential in mapping the index tumor.
Although the cost of panendoscopy is a central issue in comparing to the use of a symptom directed / radiological screening approach, the complications of the procedure itself must be taken into consideration. Although most of the papers reviewed have not had a significant number of adverse outcomes when panendoscopy is employed, complications do exist, possibly fatal, which require the patient to be knowledgeable regarding the possible unfavorable results. The most common complication involves damage to the teeth, particularly the incisors. Careful padding of the teeth, avoiding excess pressure or torque on the teeth when manipulating the scope, and proper support of the instrument itself are important in avoiding this complication. Damage to the soft tissues in the area, such as a laceration, may also occur with excessive force or misalignment of the instrument. Airway compromise is a serious complication that may result from edema or laryngospasm following manipulation during the course of the examination. In some endoscopists opinion, applying a topical anesthetic to the vocal cords may reduce the incidence of laryngospasm. If laryngospasm should occur, hyperextension of the head with positive pressure by face mask is usually all that is required for resolution. In more persistent laryngospasm, the patient may require diuretics for post- obstructive pulmonary edema in addition to positive end expiratory pressure. Pneumothorax may also occur from perforation from the bronchoscope, jet ventilating at too high of pressures, or too vigorous of a biopsy within the pulmonary system. Esophageal perforation may also occur. The clinical picture of a patient with iatrogenic esophageal perforation includes excessive sore throat immediately after the procedure, temperature spikes, subcutaneous emphysema, and tachycardia disproportionate to the fever. The chest x-ray will typically show an effusion, a widened mediastinum, and evidence of pneumoperitonitis. Therapy is directed at antibiotics, placement of drains, and closure of the defect if needed.
A paper by Hill, et al. in 1987 examined the relative risk of airway complications from patients undergoing an endoscopic procedure. In this retrospective study, the authors looked at the number of patients requiring reintubation following the surgical procedure. In their series, charts from 10,060 patients from different surgical services (otolaryngology patients excluded) were reviewed. They found that there was an incidence of .17% (17/10,060) for general surgery patients requiring reintubation for post-operative airway distress. In comparison, those patients on the otolaryngology service undergoing direct laryngoscopy alone had an incidence of 1.2% (4/324) for reintubation; furthermore, those otolaryngology patient who underwent panendoscopy had a 3% (9/302) incidence of re-intubation. Of the endoscopy otolaryngology patients (n=13) having severe airway distress, 92% (12) had undergone a laryngeal biopsy on the course of the procedure. The higher incidence of post- operative reintubation for the laryngoscopy / panendoscopy patients, especially those that had also been biopsied, was statistically significant when compared to the other surgical groups.
In a more recent study by Hendrix, et al. the risk of perioperative complications of direct laryngoscopy were reviewed retrospective in hope of ascertaining whether post-operative hospitalization for monitoring purposes was warranted. In addition, the study hope to elucidate which patients were at a greater risk for a complication. Complications were labelled as minor or major, with the major complications including esophageal perforation, pneumothorax, airway compromise (i.e. laryngospasm), EKG changes, post-operative bleeding, prolonged dysphagia, and fever. Minor complication included broken teeth, sore throat, minimal bleeding, or any complication that is not of sufficient severity to warrant admission to the hospital for adequate evaluation or treatment. The patient population was further broken down to subgroups of age, sex, body habitus, physical status level, presence of head and neck malignancy, and medical history of prior radiation therapy to the head and neck region or prior surgery in the aerodigestive tract. The incidence of major complications of the patients studied (n=200) was 19.5%, with minor complications at roughly 21%. The authors stated that the complication rates in relationship to specific patient characteristics does not allow a reliable predictor for which patients are at risk for perioperative complications. In conclusion, the authors state that direct laryngoscopy is not a trivial procedure and should require at least 24 hour observation within a hospital setting.
Toluidine blue (tolinium chloride) has found a special role in panendoscopy in allowing the physician to identify early, often occult, lesions. Savary, et. al, presented an article that states their detection of occult synchronous primaries increased from 6.4% to 25% with routine staining. Toluidine blue is a member of the thiazide group of metachromatic dyes. It has been shown to have a high affinity for both the DNA in the cell nucleus but also the RNA in the cytoplasm. It outlines the cytologic features in vivo and permits visualization of the uppermost cellular layers. The epithelium that is stained does so with an affinity and intensity that is clinically related to the number of nuclei in that unit area. Thus, areas of dysplasia / hyperplasia or frank anaplasia will be stained by the dye--allowing early detection.
The role of panendoscopy for the head and neck cancer patient will vary from institution to institution, based in part from those physician's experience from their patient population they are treating. The following is a protocol for panendoscopy drafted by Rassekh and Calhoun at The University of Texas Medical Branch at Galveston, Texas. It represents this institution's experience in properly treating the head and neck cancer patient.
Established indications for panendoscopy at this institution includes to thoroughly map or stage the index tumor, to search for multiple primary malignancies, to biopsy otherwise inaccessible lesions, and to search for an unknown primary in patients with evident cervical metastasis. Prior to the procedure, the patient needs to fully understand the reason for the procedure in addition to the possible complications that may occur. The patient, pre-operatively, will have had a routine chest x-ray, barium esophagram, and a cat scan (done pre-operatively to avoid edema artifact. It is important to instruct the patient to avoid aspirin and acetaminophen at least two weeks prior to the scheduled procedure. Coumadin should also be discontinued after appropriate consultation with the patient's primary physician. Consultation with the anesthesiologist is also an important pre-operative task, with information given regarding the estimated length of the procedure, the general assessment of the airway status, and any significant findings on physical examination or from the patient's past medical history that may impact the management of the surgical case.
Regarding the actual procedure, the patient is given decadron (10 milligrams) intravenously in anesthetic induction and also given glycopyrrolate (.1 to .2 milligrams) intramuscularly or intravenously on call to the operating room. If possible, a small endotracheal tube (5.5) is used and is orally placed. The surgeon must be present in the room prior to induction with an emergent tracheostomy set-up readily available. Following placement of the endotracheal tube, the arms are tucked to the patient's side, the table turned ninety degrees, the head wrapped with the eyes covered, and a tooth guard is placed. Prior to endoscopic procedures, visual examination of the structures of the oral cavity and pharynx are performed, in addition to manual palpation of these structures. The neck should also be carefully examined at this time. The Dedo laryngoscope is then advanced, with a thorough examination of the oral cavity, pharynx, and larynx. The tumor is carefully avoided at this time. The Dedo laryngoscope is then removed and the cervical esophagoscope is introduced. Care is taken to advance with minimal pressure and only when the lumen can be visualized. The cervical scope is then replaced with the full length esophagoscope for more distal examination. After advancing the scope to the gastroesophageal junction, it is slowly removed. While removing the scope, the mucosa is painted with toluidine blue. This is allowed to sit for two minutes at which point the scope is reintroduced and the toluidine blue solution is meticulously washed off with a 1% acetic acid solution. At this point, if any area retains the blue pigment it is carefully examined with the long zero degree telescope and a biopsy is taken.
Examination is now directed at the larynx. Using the anterior commissure scope as well as any other necessary laryngoscope, the area is examined and the mucosa of the of the entire supraglottis and hypopharynx are painted. Care is taken to avoid aspiration of the toluidine blue into the endolarynx. Again, the acetic acid solution is used to wash off the dye, and suspicious areas require more detailed inspection. For laryngeal lesions, the patient is placed into suspension for closer examination. The rigid telescopes are used to better evaluate the laryngeal structures. The zero degree scope is excellent to evaluate the arytenoids and anterior commissure. The thirty degree scope is helpful also for the arytenoids, and also the ventricles and posterior subglottis. The seventy degree scop is also helpful for the arytenoids. Photographs should be taken, using the telescopes, of the areas with lesions or abnormalities that are appreciated. While the patient is in suspension, the zero degree telescope is used to examine the trachea and the mainstem bronchi. These areas are notorious for being those regions in which the screening chest x-ray may miss a small lesion. For documented endolaryngeal lesions or for lesions noted on radiological studies, a full flexible fiberoptic examination is pursued. All suspicious lesions are biopsied, moving in a distal to proximal fashion. After completion of all biopsies, the oral cavity, oropharynx, and nasopharynx are painted with toluidine blue, with inspection and biopsy of those areas that retain the pigment. All findings must be carefully documented in the medical record.
An adaption of the above protocol is used for the patient in whom there is an unknown primary with cervical metastasis. It is important that a thorough examination of the nasopharynx is performed in these patient as an estimated 60 - 90% have nodal metastasis at the time of identification. Nonetheless, ipsilateral areas must be sampled in a caudal to rostral manner. Biopsies are obviously taken in any suspicious areas on routine physical examination as well as those areas that remain blue after toluidine blue is applied. In addition, the ipsilateral supraglottis, ipsilateral pyriform sinus, ipsilateral tongue base, ipsilateral tonsil, and the nasopharynx are also routinely done. Between biopsy samples, the cusp forceps are wiped clean. A routine chest x-ray is also performed pre- operatively, as is a barium esophogram.
Benninger MS, Enrique RR, Nichols RD: Symptom - Directed Selective Endoscopy and Cost Containment for Evaluation of Head and Neck Cancer. Head and Neck, 15: 532 - 536, 1993.
Liepzig B, Zellmer JE, Klug D; and the Panendoscopy Group: The Role of Endoscopy in Evaluating Patients with Head and Neck Cancer. Archives of Otolaryngology, 111: 589 - 594, 1985.
Atkins JP, Keane WM, Young KA, Rowe LD: Value of Panendoscopy in Determination of Second Primary Cancer. Archives of Otolaryngology, 110: 533 - 534, 1984.
Haughey BH, Gates GA, Arfken CL, Harvey J: Meta - Analysis of Second Malignant Tumors in Head and Neck Cancer: The Case for an Endoscopic Screening Protocol. Annals of Otology, Rhinology, and Laryngology, 101: 105 - 112, 1992.
Maisel RH, Vermeersch H: Panendoscopy for Second Primaries in Head and Neck Cancer. Annals of Otology, Rhinology, and Laryngology, 90: 460 - 464, 1981.
Grossman TW, Toohill RJ, Duncavage JA, Lehman RH, Malin TC: Role of Esophagoscopy in the Evaluation of Patients with Head and Neck Carcinoma. Annals of Otology, Rhinology, and Laryngology, 92: 369 - 372, 1983.
Leipzig B: Bronchoscopy in the Staging and Evaluation of Head and Neck Carcinoma. Annals of Otology, Rhinology, and Laryngology, 92: 373 - 376, 1983.
Hill RS, Koltai PJ, Parnes SM: Airway Complications from Laryngoscopy and Panendoscopy. Annals of Otology, Rhinology, and Laryngology, 96: 691 - 694, 1987.
Degregorio VY, Hobdy-Henderson KC: Tolonium Chloride as a Mucous Membrane Dye. The Annals of Pharmacotherapy, 27: 1474 - 1475, 1993.
Mc Guirt WF: Panendoscopy as a Screening Examination for Simultaneous Primary Tumors in Head and Neck Cancer: A Prospective Sequential Study and Review of the Literature. Laryngoscope, 92: 569 - 576, 1982.
Levine B, Nielsen EW: The Justifications and Controversies of Panendoscopy -- A Review. Ear, Nose, and Throat Journal, 71 : 335 - 341.
Vokes EE, Weichselbaum RR, Lippman SM, Hong WK: Head and Neck Cancer. The New England Journal of Medicine, 328 (3) 184 - 194, 1993.
Rassekh CH, Calhoun KH: Protocol -- Endoscopic Techniques in Diagnosis of Head and Neck Neoplasms.
Slaughter DP, Southwick HW, Smejkal W - Field Cancerization" in Oral Stratified Squamous Epithelium: Clinical Implications of Multicentric Origin. Cancer 1953 6:963-968