The practice of sending all non-suspect bilateral nasal polyp specimens for routine histopathology in search of unexpected diagnoses remains to be a controversial topic. The controversy can be broken down into two aspects, alteration of management and cost. Various authors had shown through their studies that there were no discrepancies between clinical and pathological diagnoses of non-suspect bilateral inflammatory nasal polyps [1, 6, 7]. As such, these authors concluded that routine examination of benign-appearing bilateral nasal polyps is perhaps unnecessary, as the findings do not alter management and incur additional financial cost. Conversely, other authors have recommended routine examination of all bilateral nasal polyps as their study series had shown unexpected findings, both benign and malignant [5, 9]. These unexpected findings arguably could have outcome-altering and medico-legal ramifications. As such, it would seem justified to perform routine examinations even though the pickup rate is low and additional cost is incurred.
For this current meta-analysis, based on eligible studies (N = 6), the pooled proportion for unexpected overall findings was 0.00599. For unexpected benign findings it was 0.00522 and 0.00107 for unexpected malignant findings. Reviewing the individual studies included, Busaba et al. study was noted to be a potential outlier. To ensure that this did not skew the results significantly and affecting subsequent calculations, a subgroup meta-analysis of the other five studies was performed. The pooled proportions from the subgroup analysis were not significantly different from the corresponding values from the general meta-analysis. Furthermore, the unexpected benign and malignant proportions from the general and subgroup meta-analyses were within each other’s confidence intervals. In other words, they were within the error of each other. This provided reassurance that including the potential outlier did not significantly skew the results and subsequent calculations.
Garavello’s study was the largest of all the studies included, examining over 2000 bilateral nasal polyp specimens. The study identified seven inverted papillomas and one adenocarcinoma. The authors concluded that occult pathology is a rare but possible event. Busaba’s study identified nine unexpected diagnoses from a total of 200 bilateral specimens (4.5 %). Of the nine unexpected findings, seven were benign and two were malignant (Table 4). Five of the seven benign findings were inverted papillomas. Three of the patients underwent revision surgeries while the other two were followed serially by nasal endoscopy. No recurrence was noted in all five patients with follow-up ranging from 2 to 5 years. The patient with squamous cell carcinoma subsequently underwent revision surgery followed by radiation therapy. The patient has remained disease-free for 3 years. The patient diagnosed with adenocarcinoma was treated with proton beam radiation therapy without additional surgery and has remained disease-free for 5 years. Given these findings, Busaba and colleagues recommended submitting all bilateral specimens for routine examination, ideally the full surgical specimen rather than samples.
Grouping all six studies together, there were 21 unexpected diagnoses (0.56 %), specifically, 18 benign (0.48 %) and three malignant (0.08 %) from a total of 3772 bilateral specimens. Of these, 16 were unexpected diagnoses of inverted papillomas, which are considered benign albeit locally aggressive. As reported, three cases underwent revision surgery while six others were only followed with serial nasal endoscopy without additional surgery. No evidence of recurrence was noted through long-term follow-up of these patients. Specific information regarding the other cases was not provided. In another study that did not meet inclusion criteria, two cases of bilateral nasal polyps yielded an unexpected finding of inverted papilloma [13]. Similarly, these cases did not require revision surgery and were followed up long-term with no evidence of recurrence. As brought forth in Romashko’s discussion, one study analyzed 33 polypectomy cases pathologically and identified foci of dysplasia and malignancy [14]. No focus was larger than 0.1 cm and no patient had evidence of recurrence with a mean follow-up of 6 years. Foci of such sizes might escape clinical detection but were identified on pathological exam. Given that there were no cases of recurrence for those patients followed with serial endoscopy from this review, this would suggest that perhaps the initial surgery was curative and patient outcome would not change if routine analysis was not performed. It is important to note that this premise of “cure” from initial surgery is based on a very small number of cases. It does however suggest the importance of regular follow-up in this population. Conversely, given the fact that there is an 8–10 % malignancy transformation rate for inverted papillomas, a contrary argument for routine examination can be made. This is on the basis that there are implications for subsequent treatment and surgery to minimize chances of recurrence or malignant transformation. A similar argument can be made as well for early pick-up of other benign entities such as sarcoidosis and granulomatosis with polyangiitis as there are implications for further work-up and early intervention that can change disease course. As reiterated within the literature, whether or not sending the specimens for routine analysis truly makes a difference in outcome for both malignant and benign entities can likely only be answered by a large prospective study.
In regards to unexpected malignant diagnoses, there were three cases noted from the review. Information regarding outcome and follow-up was only available for two of the cases [9]. In both cases, there was further treatment and long-term follow-up noted no recurrence. Given that there were unexpected malignant findings, one would argue for routine examination regardless of cost. This study aimed to provide new information by attempting to put the cost aspect into perspective. Such information is currently sparse within the literature. Data derived from a study evaluating the cost-effectiveness of colorectal screening in Canada was used for comparison purposes [15]. The incremental cost-effectiveness of low-sensitivity guaiac fecal occult blood test performed annually, fecal immunochemical test performed annually, and colonoscopy performed every 10 years, was 9159, 611, and $6133 per quality-adjusted life year respectively. Overall, the cost per quality life year from routine screening of bilateral nasal polyps appeared to be more expensive than colorectal screening. Despite this, for three of the scenarios (28, 80, and 100 % survival benefit), the cost falls well below the conventionally accepted willingness to pay cost of $50000 per life year. For the scenario of 5 % survival benefit, the cost was $64677.58, which did not differ drastically from the conventionally accepted value for willingness to pay. Such findings would suggest the practice of routine screening to be justifiable. It is important to keep in mind that the model was based on various assumptions and some perhaps considered not universally applicable. The purpose of the model was meant to generate further discussion. Ultimately, without a prospective study, it would be impossible to definitively determine the benefits for patients who are picked up due to routine examination in terms of outcomes compared to those who are missed by not sending for analyses. Currently, this review found no compelling evidence to change the practice of routine histopathologic examination of bilateral polyp specimens. As such, judgment must be utilized by the individual surgeon to determine the need to request for routine examination.
Limitations of this systematic review include the fact that it is based on a small number of studies. Furthermore, these studies were all observational studies, and as such, prone to selection bias, confounding, and the use of different selection criteria and presence of varying referral patterns among studies. The method of obtaining and submitting the surgical specimens also varied among studies. While not explicitly stated in every study, methods of obtaining specimens ranged from selective samples of whole polyps to microdebrider specimens. These different ways of obtaining the samples might result in varying representations of the specimens, potentially leading to false-negative results, ultimately affecting the true rate of pickup. The economic evaluation was limited primarily by the lack of evidence on the mortality benefit of identification of unexpected malignancies. Other limitations included the exclusion of the benefit of identifying unexpected, non-malignant diagnoses and the assumption of perfect utility in patients surviving sinonasal malignancies.
Aside from picking up occult benign and malignant diagnoses, there are other reasons proposed to submit for routine analysis. The inflammatory profile of chronic rhinosinusitis (CRS) can be subdivided into predominantly eosinophilic and non-eosinophilic/neutrophilic [16]. The disease process for the two groups is different. Eosinophilic chronic rhinosinusitis (ECRS) is often associated with greater symptom severity and poorer outcome [17–19]. ECRS requires more aggressive treatment such as the use of stronger systemic and topical corticosteroids and is often refractory to surgical management. It is also usually associated with polyps, asthma, high serum eosinophilia, aspirin sensitivity, and immunoglobulin E (IgE). Unfortunately, these findings are not consistently seen and cannot be relied upon to diagnose someone with ECRS. These studies suggested that high tissue eosinophilia from histopathological analysis of nasal polyps can serve as a marker for the diagnosis of ECRS. This in-turn can provide prognostic information and help guide specific treatment approach to optimize outcomes for ECRS patients [17]. These studies suggest that routine analysis could indeed be helpful in this regard. Notably, the pathological analysis in these studies is significantly more detailed and includes, amongst others, eosinophil count, basement membrane thickening/measurement and more detailed mucin reporting and as such, may incur higher pathological analysis-related costs than those reported in our study. Further evaluation and standardization of this indication for nasal polyp pathological evaluation is warranted.