Research ArticleClinical Studies

Value of Panendoscopy in the Identification of Synchronous Malignancies in Patients Suffering from Oral Squamous Cell Carcinoma Without Clinical Signs of a Second Primary Tumor

STEFFEN KOERDT, JAN-DIRK RAGUSE, FELIX NEUMANN, BENEDICTA BECK-BROICHSITTER, KILIAN KREUTZER, KONRAD NEUMANN, MAX HEILAND and CHRISTIAN DOLL
Anticancer Research April 2021, 41 (4) 2039-2044; DOI: https://doi.org/10.21873/anticanres.14972

Abstract

Background/Aim: The aim of the present study was to assess the value of panendoscopy of the upper aero-digestive tract in the identification of synchronous tumors in OSCC patients without clinical signs of a second primary tumor. Patients and Methods: In this retrospective study, patients diagnosed with a primary OSCC who received surgical therapy between January 1st, 2012 and December 31st, 2017 were included. Participants must have undergone panendoscopy during the staging process. None of these patients showed clinical signs of a second primary tumor. Results: A total of 265 patients (99 females and 166 males; mean age=63.3 years, range=26-96 years) were included. The mean (SD) follow-up was 25.88 (±20.479 SD) months. Five synchronous secondary tumors (1.9%) could be identified within this cohort. Of these, only two (0.8%) were located within the area of panendoscopy and were diagnosed in patients with regular alcohol and/or tobacco abuse. Eighteen metachronous second primary tumors were diagnosed, 10 being located within the upper aero-digestive tract. Conclusion: The relevance of routinely performed panendoscopy in patients suffering from an oral squamous cell carcinoma without clinical signs of a secondary tumor should be critically re-evaluated, especially in patients without typical risk factors.

Key Words:

Oral cancer is one of the most common newly-diagnosed malignancies worldwide and has a high mortality rate (1). Histologically, about 90% of all cases of oral cancer are oral squamous cell carcinomas (OSCCs) (2). In an individual and guideline-based therapeutic approach, primary surgical treatment, combined with radiation and chemotherapy in advanced stages, is considered to be the gold standard (3).

Etiologically, OSCC is caused by abuse of nicotine and alcohol in the majority of cases. For instance, heavy smokers have a 20-fold higher risk of suffering from OSCC. In particular, the combination of alcohol and tobacco leads to a multiplicative risk that is greater than the joint risk for OSCC (4). These and other OSCC-related factors also increase the risk of suffering from other syn- or metachronous malignancies in the upper aero-digestive system. Therefore, at the time of initial diagnosis, complete staging is inevitable. Besides histological evaluation of the primary lesion, computed tomography (CT) or magnetic resonance imaging (MRI) scans examining possible regional and distant metastases are an important part of standard staging procedures to identify patients with secondary malignancies.

Panendoscopy has been established in routine clinical practice in the staging process of OSCC patients. Panendoscopy aims to generate an exact assessment of the known tumor, while also potentially identifying synchronous malignancies. Although there is no consensus on the scope of a panendoscopy, it typically involves examination of the oral cavity, the naso- and oropharynx, the hypopharynx, and the larynx under general anesthesia, which is typically performed as an inpatient procedure in Germany. To avoid unnecessary harm to patients and a waste of limited health care system resources, the role of routine panendoscopy during the staging process in patients with OSCC is currently under debate. According to national guidelines, “an ENT examination, and possibly an endoscopy, must be performed as part of the primary diagnostic investigation of oral cavity carcinoma” (3). In its most current (but not recently revised) version, the indications for panendoscopy also only include cases with an increased risk of secondary carcinomas in the medical history or suspicious findings in initial radiological staging (5).

Previous studies emphasize the high risk of synchronous primary tumors in patients suffering from head and neck cancer, especially in patients with typical risk factors like tobacco use and alcohol abuse (6-9). However, recent publications show low rates of synchronous second primary tumors diagnosed in patients staged under current guidelines, questioning the efficiency of the routine use of panendoscopy in all these patients (10-12). Looking at the current literature dealing with early-stage OSCC patients or OSCC patients without typical risk factors, the rate of synchronous second primary tumors is even less than 1% (13, 14).

Improvements of radiological techniques and the supposedly low rate of synchronous primary tumors in patients suffering from OSCC, as described, calls routine panendoscopy into question, especially in patients without history of smoking or patients in the early stages of the disease. Therefore, the aim of the present study was to present panendoscopy data used to identify synchronous malignancies in patients with OSCC and without clinical signs of a secondary tumor, and to discuss the value of this method in the routine staging process.

Patients and Methods

Ethics statement. This retrospective study followed the Declaration of Helsinki on medical protocol and ethics, and local ethical regulations (EA2/077/20).

Study design and patients. A retrospective data analysis was performed including patients with primary OSCC receiving surgical therapy between January 1st, 2012 and December 31st, 2017, who had undergone (rigid or flexible) panendoscopy during the staging process. All patients were treated in the Department of Oral and Maxillofacial Surgery at Charité – Universitätsmedizin Berlin. Patients who suffered from previous head and neck cancers or other tumor diseases 5 years before diagnosis of OSCC were excluded from the study. Patients with previous radiotherapy in the head and neck region were also excluded. Patient data and disease characteristics were collected from a review of patient records. In case of missing data, the patient was excluded. Staging was conducted according to national guidelines at the time of diagnosis (3). Panendoscopy typically involved the examination of the oral cavity, the naso- and oropharynx, the hypopharynx, and the larynx. Bronchoscopy and/or esophagoscopy was not routinely performed. A second primary tumor was classified as synchronous if it was diagnosed within 6 months of the first primary tumor diagnosis and as a metachronous second primary tumor if it was detected later, respectively at a different localization than the first primary tumor.

Statistical analysis. All data were analyzed by using IBM® SPSS® for Mac (version 27.0; IBM Corp., USA). Means and standard deviations (SD) were calculated. Sensitivity and specificity with two-sided 95% confidence intervals were calculated as well.

Results

In this study, 265 patients (99 females and 166 males; mean age 63.3 years, ranging from 26 to 96 years) who were diagnosed with a primary OSCC between January 1st, 2012 and December 31st, 2017 were included. At the time of presentation, no participants showed clinical signs of a second primary tumor.

The mean (±SD) follow-up of all patients was 25.88 (±20.479) months, ranging from 0 to 84 months. In total, five synchronous tumors (Table I) could be identified during the observation period.

View this table:
Table I.

Characteristics of all patients suffering from a synchronous carcinoma.

The occurrence of synchronous malignancies in relation to clinical and primary tumor-related characteristics are summarized in Table II. In 19 of the 265 included cases (7.2%), a biopsy was performed due to a suspicious lesion during panendoscopy. A carcinoma of the posterior portion of the uvula was histologically confirmed in only one case. CT showed no evidence of synchronous primary malignancies in any of the biopsied cases. None of the 265 evaluated cases showed evidence of synchronous second malignancies in both, CT and panendoscopy.

View this table:
Table II.

Frequencies of synchronous malignancy in relation to clinical and primary tumor-related characteristics.

During the observation period, a total of 18 metachronous second primary tumors (mean time to diagnosis: 32.56 months, range 11 to 80 months) were diagnosed, 10 being located within the upper aero-digestive tract (mean time to diagnosis: 34.60 months, range 11 to 80 months) (Table III).

View this table:
Table III.

Characteristics of all patients suffering from a metachronous carcinoma.

In terms of specificity and sensitivity, the sensitivity was 100% (95%CI=2.5-100) and specificity was 93.2% (95%CI=89.4-95.9).

Discussion

Staging procedures in OSCC include CT or MRI scans of the site of the primary tumor and the neck, as well as the thorax and the upper abdomen. However, current national guidelines do not include a specific recommendation on the use of panendoscopy to identify patients with synchronous malignancies (3). Nevertheless, despite specific instructions, panendoscopy of the upper aerodigestive tract has been established even in unsuspicious cases without clinical or radiological evidence of synchronous tumors. The aim of this study was to retrospectively evaluate incidences of synchronous malignancies in primary diagnosed OSCC and to correlate these findings with radiological assessments and findings from the panendoscopy.

In routine clinical practice, panendoscopy has been established in the staging process of OSCC patients. A total of 265 patients with histologically confirmed primary OSCC who underwent routine staging procedures with panendoscopy were included in the present study. Five synchronous secondary tumors (1.9%) were identified in the cohort, in accordance with reports from the literature. In 2015, Koo et al. described one synchronous malignancy in a study group of 112 early-stage tongue OSCC (13). Furthermore, a study by Metzger et al. in 2019 revealed only three synchronous malignancies of the upper-aerodigestive tract in 484 OSCC patients, corresponding to 0.6% of the cohort (14).

Of the five synchronous second primary tumors observed in this study, two were located within the aero-digestive tract and were thus reachable by panendoscopy. One lesion, which was located at the uvula, was not clinically conspicuous before, but could be detected at the time of panendoscopy. A carcinoma of the esophagus could not be detected at the time of panendoscopy because esophagoscopy is not routinely performed in our department. This carcinoma was diagnosed about 6 weeks after panendoscopy, when it had become clinically apparent by emesis. Considering these two cases, the prevalence of synchronous second primary tumors within the panendoscopy area was 0.8%. Both patients had a history of regular alcohol and/or tobacco abuse. This might lead to the conclusion that panendoscopy is not necessary in patients without typical risk factors lacking symptoms of a second primary tumor.

The three other synchronous second primary tumors were located in the lung, the rectum, and the sigmoid colon. The carcinoma of the lung was detected by performing a CT of the lung, followed by a bronchoscopy and a histological biopsy of the lung mass. It was not clinically apparent. The (clinically unapparent) rectal carcinoma was detected by performing routine sonography of the abdomen during the staging process, followed by coloscopy with biopsy. Finally, the carcinoma of the sigmoid colon became clinically apparent during the clinical course by emesis and obstipation, leading to diagnosis.

A study by Kesting et al. from 2009 evaluates the use of esophagogastroduodenoscopy in patients with primary OSCC. In a study population of 570 patients, a statistically significant association was found between the advanced and limited tumor stage for Barrett’s esophagus, so that this study group advocates the use of esophagogastroduodenoscopy in the routine staging workup for primary OSCC (15). Bronchoscopy was also evaluated in another study by the same group (16). Herein, malignancies of the lung were found in 2% of examined patients. Nevertheless, additional diagnostics, such as bronchoscopy and esophagogastroduodenoscopy, seem useful in certain patient groups, whereas the routine use in low-risk profile patients with limited disease does not seem reasonable. As panendoscopy is usually conducted under general anesthesia as an inpatient procedure, along with CT or MRI scans and biopsies of the primary tumor, resources are being stressed. However, invasive procedures involving a general anesthesia, such a panendoscopy, are also accompanied by perioperative risks, such as fistulas or unplanned tracheostomy (17). Nevertheless, panendoscopy has its eligibility in cancers of unknown primary (CUP) (18), evaluation of the extent of the primary tumor, and in assessing the suitability of transoral robotic surgery (10). We advocate a risk stratification of patients according to the initial tumor size, other medical conditions, clinical symptoms, and existing risk factors.

In addition to panendoscopy, staging procedures can be expanded by using positron emission tomography (PET) combined with CT scans (PET-CT). PET-CT plays a remarkable role as a diagnostic tool in patients with OSCC in particular and in head and neck malignancies in general. In particular, it has become a standard procedure in the diagnosis of recurrent disease. The value of PET-CT in primary staging of OSCC has been evaluated in several studies. Al-Ibraheem et al. stated that the sensitivity of PET-CT is equivalent to MRI or CT in staging procedures of the primary tumor (19). Moreover, Su et al. identified a pooled sensitivity of 84% and a pooled specificity of 93% for PET-CT in the detection of metastatic lymph nodes (20). Furthermore, as whole-body scan, PET-CT offers the opportunity of distant metastasis detection. Su et al. found a pooled sensitivity of 82.2% and a pooled specificity of 95.1% in initial staging of distant metastasis (20). Moreover, Haerle et al. compared PET-CT and panendoscopy with respect to synchronous second primary tumors (21) and found a sensitivity of 74% and a specificity of 99.7% for panendoscopy, but also a sensitivity of 100% and a specificity of 95.7% for PET-CT. According to those findings, PET-CT may be considered as a useful addition in the staging of primary OSCC. Sensitivity and specificity in the current study, however, were comparable with 100% and 93.2% respectively.

Taken together, the results of the current study indicate a low prevalence of synchronous second primary cancer in OSCC patients without clinical signs of a secondary tumor, especially in the upper aero-digestive tract. Based on our findings, panendoscopy should not be applied as a diagnostic procedure in all patients. Since both patients diagnosed with a synchronous malignancy located within the aero-digestive tract and were thus reachable by panendoscopy had typical risk factors, a risk-oriented approach should be considered. Besides the fact, that this current study calls for a new adoption of panendoscopy in the routine staging of OSCC, limitations of this study lie within the individual assessment of panendoscopy results and the retrospective character of the study.

In conclusion, we identified a low prevalence of synchronous second primary carcinomas in patients with primary OSCC, especially in the upper aero-digestive tract detectable by panendoscopy. In patients without typical risk factors, we did not observe any synchronous tumors. Therefore, routine panendoscopy in patients suffering from OSCC without risk factors or clinical signs of a second malignancy should be reevaluated. This may lead to fewer morbidities and lower treatment costs.

Acknowledgements

This study is part of the doctoral thesis of Felix Neumann.

Footnotes

  • Authors’ Contributions

    SK, JDR, and CD conceived the study. FN collected the data; KN performed statistical analysis. SK and CD wrote the original draft of the manuscript; BBB, KK, JDR, and MH revised subsequent drafts and approved the final draft for submission. All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare regarding this study.

  • Received January 18, 2021.
  • Revision received February 24, 2021.
  • Accepted February 25, 2021.

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Value of Panendoscopy in the Identification of Synchronous Malignancies in Patients Suffering from Oral Squamous Cell Carcinoma Without Clinical Signs of a Second Primary Tumor
STEFFEN KOERDT, JAN-DIRK RAGUSE, FELIX NEUMANN, BENEDICTA BECK-BROICHSITTER, KILIAN KREUTZER, KONRAD NEUMANN, MAX HEILAND, CHRISTIAN DOLL
Anticancer Research Apr 2021, 41 (4) 2039-2044; DOI: 10.21873/anticanres.14972
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