Abstract
Respiratory epithelial adenomatoid hamartoma (REAH) is a rare lesion located mostly in the anterior and upper parts of the nasal cavity, caused by pseudo-glandular proliferation of the respiratory epithelium, enriched with goblet cells. The stroma is characterized by a dense infiltrate composed mainly of mast cells. Previous studies have indicated a strong association between REAH located in the olfactory area and allergic rhinitis. We present the case of a 48-year-old man with a history of NSAID-exacerbated respiratory disease (N-ERD) who underwent surgical removal of a lobed, cerebriform, yellowish-pink mass from the right olfactory region. Also, bilateral inflammatory nasal polyps were removed. We discuss the still-unclear etiopathogenesis of REAH, the challenges of diagnosing this rare lesion, and the role of N-ERD in the development and growth of this condition. We propose that REAH can be understood as a rare tumor lesion, formed based on local developmental anomalies, the growth of which requires stimulation by inflammatory mediators. Although there is a high degree of association between REAH and allergic rhinitis, this case indicates that this lesion can also occur in patients with N-ERD.
Introduction
Respiratory epithelial adenomatoid hamartoma (REAH) is a rare clinical entity located in the sinonasal area in the form of a polypoid soft tissue growth, which was first described by Wenig and Heffner in 1995.1,2 According to the World Health Organization International Classification of Tumors of the Head and Neck, it is classified among benign tumors. 3 However, the origin of REAH has not yet been sufficiently investigated.
The name “hamartoma” indicates that the lesion occurs due to the appearance of developmental anomalies in the tissues from which the growth originates.3,4 On the other hand, a frequent association of the occurrence of REAH and chronic inflammatory diseases of the nasal mucosa and paranasal sinuses, including chronic rhinosinusitis (CRS) and allergic rhinitis, was observed.4–6 The word “adenomatoid” would indicate the fact that REAH consists of glandular formations. In fact, REAH represents the proliferation of pseudo-glandules in the form of many folds of respiratory epithelium from the surface of the nasal mucosa.2–6 REAH is somewhat more frequent in the male population, and can be found in all age groups, although it is most frequent in the 4th and 5th decades of life.2–6
Non-steroidal anti-inflammatory drug (NSAID) – exacerbated respiratory disease (N-ERD) is a distinct clinical entity within CRS with nasal polyps (CRSwNP). 7 It represents the triad of severe relapsing CRSwNP, hypersensitivity to NSAIDs, and usually difficult-to-control non-allergic asthma. 7 Although it has not yet been fully investigated, it is believed that the disease is associated with a disturbance in the metabolism of arachidonic acid, and, after taking one of the NSAIDs, symptoms can appear in the entire respiratory tract.7,8
The association of REAH and N-ERD is rarely observed in clinical practice. Here we present the case of a patient with N-ERD, in whom the diagnosis of REAH was established after histological analysis of the surgically removed lesion.
Methods
This is a case report, and the presentation of this study conforms to the CARE guidelines. 9 Patient was randomly selected during our clinical practice. The patient gave written informed consent for treatment, to participate in this study, and for his anonymized information to be published in this article. The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2024. As this study involved human participants, it was reviewed and approved by the Ethics Committee of the Military Medical Academy, Belgrade, Serbia (Approval number 21/2022) from June 01, 2022.
Case presentation
Patient information
All patient details have been de-identified. A man in his fifties came for an ear, nose, and throat (ENT) examination in the Outpatient Department of the Military Medical Academy, Belgrade, Serbia, in October 2024. His complaints were difficulty breathing through the nose, increased thick secretions from the nasal cavity, discharge of secretions into the pharynx, pain, and pressure in the area of the face and the right half of the forehead. Symptoms started four years ago with nasal obstruction, sneezing, watery nasal discharge, and impaired sense of smell. The skin prick test with inhaled allergens did not show hypersensitivity. There were no familial, genetic, or psycho-social details that would suggest the pathological condition of this patient. He was treated with a combination of intranasal antihistamine and corticosteroid (azelastine-hydrochloride 137 µg with fluticasone propionate 50 µg intranasal spray, two times daily) with occasional interruptions throughout. The patient stated that two years ago, after taking ibuprofen for a headache, there was an attack of coughing, choking, and sneezing. A year before coming to the ENT examination, the patient noticed that his nasal breathing was getting worse, he completely lost his sense of smell, and pain and pressure appeared in his face and forehead. On a couple of occasions, he had an episode of light bleeding from the right side of the nose.
Clinical findings
Laboratory findings showed an increased percentage of eosinophils in the blood (12.6%), while total serum immunoglobulin E (IgE) was 293.5 IU/mL. Two weeks after stopping the use of antihistamines and corticosteroids, the skin prick test with inhaled allergens was repeated, but again did not show a positive finding. Pulmonology diagnostics suggested asthma caused by hypersensitivity to NSAIDs. Endoscopic examination revealed polypoid growths in both sides of the nasal cavity, with more on the right side of the nasal passage. A computed tomography (CT) scan of the paranasal sinuses showed complete opacification of both ethmoid labyrinths and the right frontal sinus, partial opacification of the nasal cavities, and thickened mucosa of the maxillary sinuses. An enlargement of the right olfactory cleft and a pushing of the nasal septum to the left side were also observed, and, according to the radiologist’s evaluation, the dimension of the right olfactory cleft was 11 mm (Figure 1). Deformation of the left olfactory cleft was also observed, but the width was below 10 mm (Figure 1). A computed tomography scan of the paranasal sinuses showing complete opacification of both ethmoid labyrinths and the right frontal sinus, partial opacification of the nasal cavities, and thickened mucosa of the maxillary sinuses. An enlargement of the right olfactory cleft and a pushing of the nasal septum to the left side were also observed (arrowhead).
Therapeutic intervention
Endoscopic ethmoidectomy and polypectomy were performed under general anesthesia. A difference was observed in the macroscopic appearance of the material removed from the right side of the nasal cavity. One part of the material consisted of typical inflammatory polyps with their semi-transparent, edematous, smooth, and poorly blood-stained surface. The other mass removed from the right olfactory region was a yellowish-pink, lobed, rough lesion, weakly transparent, and well-vascularized with a cerebriform appearance (Figure 2). On the left side of the nasal cavity, only polypoid masses were found. Pathohistological analysis of most of the material indicated inflammatory nasal polyps with very edematous stroma and dense eosinophilic infiltrate (Figure 3). Analysis of the lobed, yellowish-pink mass showed the presence of deep folds of respiratory epithelium, very rich in goblet cells, in the form of pseudo-glandules, while the stroma was densely infiltrated with mast cells and eosinophils. Immunohistochemical analysis after Alcian blue staining showed the presence of cylindrical respiratory epithelial cells with goblet cells filled with secretion. Cytokeratin 7 (CK-7) staining indicated a low degree of keratinization in the respiratory epithelial cells, while Ki-67 staining indicated a low level of proliferation in the epithelium, thus confirming the benign nature of the lesion (Figure 4(a)–(d)). The patient was discharged from the hospital after 4 days of good endoscopic findings, with instructions to regularly rinse the nasal cavities with saline solutions two times daily and intranasal corticosteroid spray therapy (mometasone-furoate nasal spray, two sprays of 50 µg in each nostril in the morning). The mass removed from the right olfactory region was a yellowish-pink, lobed, rough lesion, weakly transparent, and well-blooded with a cerebriform appearance. Pathohistological finding of the removed inflammatory nasal polyp showing the hypertrophy of pseudostratified respiratory epithelium, thickening of the basement membrane, stromal edema with rich inflammatory infiltrate composed mainly of eosinophils (Hematoxylin-eosin staining, magnification x 200). (a) Analysis of the lobed, yellowish-pink mass showed the presence of deep folds of respiratory epithelium, very rich in goblet cells, in the form of pseudo-glandules, while the stroma was densely infiltrated with mast cells and eosinophils (Hematoxylin-eosin staining, magnification x 100). (b) Immunohistochemical analysis after Alcian blue staining showed the presence of cylindrical respiratory epithelial cells with goblet cells filled with secretion (magnification x 100). (c) Cytokeratin 7 (CK-7) staining indicated a low degree of keratinization in the respiratory epithelial cells (magnification x 100). (d) Ki-67 staining indicated a low level of proliferation in the epithelium, thus confirming the benign nature of the lesion (magnification x 100).
Follow-up and outcomes
After that, he regularly came for follow-ups, and 9 months after the surgical treatment, his quality of life improved significantly, with normal breathing through the nose, a relatively preserved sense of smell, and normal endoscopic findings in the nasal cavity. In doing so, the patient states that he regularly washes his nose with saline solutions and uses an intranasal corticosteroid spray.
Discussion
According to earlier histological studies, inflammatory nasal polyps were classified into 4 categories: eosinophilic or edematous polyps, fibroinflammatory polyps, glandular polyps, and polyps with cellular atypia.10,11 Starting in 2005, the World Health Organization established a separate diagnosis for glandular polyps, known today as REAH. 12 However, a group of French authors headed by Roger Jankowski distinguishes two categories: REAH and REAH-like lesions, which represent REAHs associated with nasal polyposis, which is usually found in previously operated patients.13–15 REAH should be fully differentiated from CRSwNP. CRSwNP is a form of CRS characterized by the presence of inflammatory polyps originating from different meatuses (middle meatus and superior meatus).16,17 In Caucasians, it is a T2 cytokine profile with high tissue eosinophilia, elevated blood eosinophilia, and elevated total IgE in both tissue and blood.16,17 NSAID intolerance is a more severe form of CRSwNP that can be difficult to treat, is often associated with asthma, and recurs after surgery.16,17 However, as in our patient, N-ERD is not associated with allergic rhinitis, but is a consequence of a disorder in the metabolism of arachidonic acid, which leads to the accumulation of proinflammatory leukotrienes in the mucosal tissue of the upper and lower respiratory tract.7,8 Hamartomas are slowly growth lesion. There are four different types of hamartomas according to the histology: REAH, seromucinous hamartoma (SH), chondro-osseous type of REAH (COREAH), and nasal chondromesenchymal hamartoma (NCMH).18,19
The origin of REAH is not well researched. Its appearance in the nasal cavity is associated with various factors, such as genetic disorders, developmental anomalies, and chronic inflammation. Although REAH is a benign lesion, Ozolek and Hunt, comparing the genetic profile of patients with REAH and nasal sinus adenocarcinoma, found certain similarities, even suggesting that REAH could be a precursor of adenocarcinoma. 20
Today, most authors believe that chronic inflammation is necessary for the appearance and development of REAH. Also, the localization of REAH could be related to the inflammatory origin of REAH. In general, REAH can be a unilateral or bilateral lesion. Bilateral REAH is usually located on the mucosa of the upper part of the nasal septum, the olfactory region, the middle, and upper nasal turbinates.3,4 Unilateral REAH can usually grow from the inferior parts of the nasal septum, from the inferior turbinate, or from the floor of the nasal cavity.3,4 Issa et al. 21 indicate that inflammatory nasal polyps can be found in close to 50% of patients who underwent surgical removal of REAH. Vukomanović Đurđević et al. 22 found an association of REAH with chronic inflammation of the nasal mucosa in as many as 70% of cases, most often with perennial allergic rhinitis. Bilateral lesions originating from the olfactory region were in over 87% of cases associated with inflammatory nasal polyps. 21 In the largest series of 88 patients with REAH to date, Fischer et al. 23 found an association of the bilateral olfactory cleft REAH with allergic rhinitis in 67.3%, and with asthma in 55.1% of patients. Some authors believe that the high level of association of bilateral REAH located in the olfactory region with allergic rhinitis indicates the possibility that REAH could be one of the manifestations of the so-called central compartment atopic disease (CCAD). 24 However, apart from being mentioned in one publication, this claim has never been proven. It is actually more correct to say that bilateral REAH of the olfactory region resembles CCAD in terms of clinical characteristics. So, it is very important to make a clear distinction between allergic rhinitis, CCAD, and REAH. CCAD, according to the last EPOS guideline and other studies, is a distinct clinical entity within CRS in which inflammatory polypoid lesions are localized in the central and upper parts of the nasal cavity.16,24,25 It is related to the flow of air through the central parts of the nasal cavity.16,24,25 In patients who are hypersensitive to inhaled allergens, these seasonal and perennial allergens leave their inflammatory mark precisely in the area of the nasal septum and nasal turbinates.16,24,25 In our patient, in addition to the olfactory region, inflammatory changes also affected the ethmoidal cells, as well as the right frontal sinus. Polypoid hyperplastic growths of the nasal mucosa interfere with ventilation and drainage in the ethmoid cells, which causes inflammatory changes in their mucosa. Given that the frontal sinus is ventilated and drained via the ethmoidal region, retention of secretions occurred in it as well. Hypersensitivity tests with inhaled allergens were negative in our patient. On the other hand, an increased percentage of eosinophils in the blood, as well as high values of total serum IgE, indicate that our patient is dominated by inflammation of the T2 type of immune response. CRS in patients with N-ERD is, in the vast majority of cases, a difficult-to-control disease, prone to recurrence of nasal polyps. 26 It is characterized by the production of large amounts of inflammatory mediators, as well as growth factors and enzymes.26–28 In addition to T2 cytokines, including interleukins (IL-4, IL-5 and IL-13), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), as well as enzymes released from mast cells and eosinophils, primarily tryptase, mayor basic protein (MBP), eosinophil cationic protein (ECP) and matrix metalloproteinases, play an important role in the driving of chronic inflammation.26–28 All these factors lead to the conditions for the remodeling of the nasal mucosa and the formation of nasal polyps, representing targets for the application of biological therapy.26–28 On the other hand, it is assumed that inflammatory mediators condition the proliferation of the epithelium and mesenchyme, leading to angiogenesis and thereby creating conditions for the growth of REAH. 29 REAH is not a rare lesion in the nasal cavity. They can be isolated growth tumors in the olfactory cleft, unilateral or bilateral, or be associated with inflammatory nasal polyps. 13 Typically, when they are associated with nasal polyposis, they are diagnosed during a recurrence of the disease after surgery. 13 Histology of the lesions present lateral to the middle turbinate and medial to the middle turbinate is necessary to diagnose the REAH in the olfactory cleft and polyps in the ethmoid. 13 Such a case with primary non-surgical nasal polyposis as the initial presentation is less common.
To make a definitive diagnosis of REAH, it is necessary to have an experienced pathologist. However, sometimes it is needed to apply additional immunohistochemical staining in addition to the standard staining with the hematoxylin-eosin (HE) technique. Apart from inflammatory nasal polyps, inverted papilloma, and sinonasal adenocarcinoma, in which differences compared to REAH can already be observed based on the HE staining technique, it is somewhat more challenging to distinguish between REAH and SH, which is also primarily located in the sinonasal region.3,19,30 Unlike REAH, which is most often localized in the front and upper parts of the nasal cavity, SH is mainly represented in the back part of the nasal passage.3,19,30 REAH is a pseudo-glandular proliferation in which, in addition to cylindrical ciliated epithelial cells, there are numerous goblet cells. SH is a benign proliferation composed of true small eosinophilic glands. Most data in this direction can be provided by staining with the Alcian blue technique, which visualizes glandular cells very well.3,19,30
Conclusion
At the current level of science and according to the current classification of benign lesions of the head and neck, REAH can be understood as a rare tumor lesion, formed based on local developmental anomalies, the growth of which requires stimulation by inflammatory mediators. Although it is known that there is a high degree of association between REAH and allergic rhinitis, this case indicates that the occurrence of this lesion is also possible in patients with N-ERD. However, the true origin of this rare lesion has not yet been well investigated, so further investigations in the fields of rhinology, genetics, pathophysiology, and pathology are necessary.
Patient perspective
Nine months after the end of treatment, the patient is a happy man who leads a normal life, with caution regarding the use of NSAIDs. He regularly uses his local therapy and comes for regular check-ups. The doctor explained to him the nature of the disease, the degree of its aggressiveness, and the possibility of relapse.
Ethical considerations
As this study involved human participants, it was reviewed and approved by the Ethics Committee of the Military Medical Academy, University of Defence, Belgrade, Serbia (Approval number 21/2022), June 01,2022.
Footnotes
Acknowledgements
This study was performed as a part of the scientific project of the Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia (MFVMA02/23-25/)
Consent to participate
Written informed consent was obtained from the patient to participate in this study.
Consent for publication
Written informed consent was obtained from the patient for their anonymized information to be published in this article.
Author contributions
All authors contributed to the study’s conception and design. The idea of the article was proposed by A.P. Diagnosis of the patient, literature search, data analysis, and drafting of the article were performed by A.P., L.J., J.S., and B.V.Đ. A.P., L.J., J.S., and B.V.Đ performed a critical review.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
All relevant data supporting the findings of this case report are included within the article. Additional information regarding this case may be available from the corresponding author upon reasonable request, subject to patient confidentiality. The patient’s identity has been anonymized.