RESPIRATORY EPITHELIAL ADENOMATOID HAMARTOMA (REAH): UNCOMMON NASAL POLYPS MASQUERADER - EVALUATION AT HOSPITAL CHANCELLOR TUANKU MUHRIZ, MALAYSIA

Background Respiratory epithelial adenomatoid hamartomas (REAH) are uncommon, benign glandular growths occurring in the nasal cavity, paranasal sinuses, and nasopharynx. This study seeks to deepen our knowledge of REAH by presenting eight cases along with a review of relevant literature. Methods A retrospective review was performed on all patients with biopsy-proven REAH from 2012 – 2023. Lesions were biopsied endoscopically and sent for histopathological analysis. Data was collected with respect to demographic (age, gender), clinical presentation (symptoms, duration, endoscopic findings), imaging, histopathology, treatment, and outcomes. Results Between 2012 and 2023, our center identified 8 cases of histopathologically confirmed REAH out of 339 nasal biopsies (2.4%), with an equal distribution of men (n = 4) and women (n = 4), and a mean age of 55.6 years. All patients presented with nasal obstruction, with two experiencing additional symptoms: one had epistaxis and another had anosmia. Three patients (37.5%) had isolated, unilateral REAH, while five (62.5%) had REAH associated with chronic rhinosinusitis, presenting both unilaterally and bilaterally. All underwent successful endoscopic excision, with no recurrence, and 5 (62.5%) had radiological evaluation showing hypodense lesions without bony erosion. Conclusion REAH is a benign glandular proliferation of the nasal cavity, confirmed through histopathology, and often curable with surgical resection. Clinically, it presents as rubbery, non-vascular polypoid masses, while radiologically, it appears as exophytic homogeneous lesions without bony erosion and olfactory cleft widening over 10 mm. Recognizing these features can help prevent unnecessary or overly aggressive treatments. RESPIRATORY EPITHELIAL ADENOMATOID HAMARTOMA (REAH): UNCOMMON NASAL POLYPS MASQUERADER - EVALUATION AT HOSPITAL CHANCELLOR TUANKU MUHRIZ, MALAYSIA

The authors would like to thank the Department of Otorhinolaryngology–Head and Neck Surgery and the Department of Pathology, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia, for their kind support and collaboration in this study. We also extend our appreciation to all patients and clinical staff involved in their care.

Respiratory epithelial adenomatoid hamartomas (REAH) are uncommon, benign glandular growths occurring in the nasal cavity, paranasal sinuses, and nasopharynx. This study seeks to deepen our knowledge of REAH by presenting eight cases along with a review of relevant literature.

A retrospective review was performed on all patients with biopsy-proven REAH from 2012 – 2023. Lesions were biopsied endoscopically and sent for histopathological analysis. Data was collected with respect to demographic (age, gender), clinical presentation (symptoms, duration, endoscopic findings), imaging, histopathology, treatment, and outcomes.

Between 2012 and 2023, our center identified 8 cases of histopathologically confirmed REAH out of 339 nasal biopsies (2.4%), with an equal distribution of men (n = 4) and women (n = 4), and a mean age of 55.6 years. All patients presented with nasal obstruction, with two experiencing additional symptoms: one had epistaxis and another had anosmia. Three patients (37.5%) had isolated, unilateral REAH, while five (62.5%) had REAH associated with chronic rhinosinusitis, presenting both unilaterally and bilaterally. All underwent successful endoscopic excision, with no recurrence, and 5 (62.5%) had radiological evaluation showing hypodense lesions without bony erosion.

REAH is a benign glandular proliferation of the nasal cavity, confirmed through histopathology, and often curable with surgical resection. Clinically, it presents as rubbery, non-vascular polypoid masses, while radiologically, it appears as exophytic homogeneous lesions without bony erosion and olfactory cleft widening over 10 mm. Recognizing these features can help prevent unnecessary or overly aggressive treatments.

Nasal polyps Nasal obstruction Epistaxis Papilloma Hamartoma Epithelium KEYPOINTS 1. Respiratory epithelial adenomatoid hamartoma (REAH) is a rare benign glandular lesion of the sinonasal tract that can mimic nasal polyps and inverted papilloma, leading to diagnostic delay or mismanagement. 2. A 10-year retrospective review (2012–2023) at Hospital Canselor Tuanku Muhriz identified eight histopathologically confirmed cases of REAH, representing 2.4% of all nasal biopsies. 3. Nasal obstruction was the predominant symptom; radiologic findings showed exophytic, hypodense lesions without bony erosion and olfactory cleft widening >10 mm, aiding in preoperative suspicion. 4. Histopathology demonstrated glandular proliferation of ciliated respiratory epithelium with a thickened basement membrane, distinguishing REAH from inflammatory polyps, inverted papilloma, and low-grade adenocarcinoma. 5. Endoscopic surgical excision achieved complete resolution in all patients, with no recurrence, underscoring the value of accurate diagnosis and conservative surgical management.

The pathological definition of a hamartoma, irrespective of site of origin, is an abnormal proliferation of tissue indigenous to the organ to create a mass or tumor. 1 The term “hamartoma” derived from the Greek “hamartia” meaning defect. 2 Hamartomas can arise in various body parts, particularly in the lungs and abdominal cavity, rarely in the head and neck region, where they may occasionally appear in the soft tissues of the oral mucosa and neck. 3 REAH, a type of uncommon hamartoma in the upper aero-digestive tract, was first identified by Wenig and Heffner in 1995. The nasal cavity, particularly the posterior septum, accounts for 70% of REAH cases, peak incidence between the third and eighth decades with a 7:1 male predilection. 4 Since Wenig’s initial series, most literature on REAH has focused on case reports and histopathological studies, leaving its pathogenesis, imaging characteristics, and clinical significance largely unexplored. Recent studies have also challenged some of the originally identified distinguishing features, noting that REAH often appears alongside inflammatory processes as well as in isolation. 5 Histopathologically, REAH is characterised by glandular proliferation of respiratory epithelium in the nasal cavity, sinuses and nasopharynx that invaginate into the submucosa. The glandular component is derived from the surface nasopharyngeal epithelium and not from the seromucinous glands. 3 Unlike REAH, nasal polyps lack glandular proliferation and epithelial invagination, and typically have a thickened basement membrane, which is absent in REAH. Other important differential diagnoses include inverted Schneiderian papillomas and low-grade adenocarcinomas. These more aggressive lesions can resemble REAH macroscopically, especially in solitary forms, making histological analysis essential. Inverted papillomas feature invagination of hyperplastic squamous or respiratory epithelium with a thin basement membrane, a characteristic absent in REAH but challenging for less experienced pathologists to identify. 6

The records of 8 patients with a histopathologically confirmed REAH were identified from a retrospective data review of nasal biopsies from Hospital Canselor Tuanku Muhriz (HCTM) Universiti Kebangsaan Malaysia. Data collected included age, gender, smoking status, clinical presentation, laterality, site of involvement, imaging studies, treatment and outcomes. (Table 1) Based on the duration of symptoms, a “symptoms duration” score was given. (Table 2) Student t test was performed to assess significance between mean age and symptoms duration. Fischer’s exact test was used to analyze significant differences between categorical values (gender, sex, smoking history, presenting symptoms with duration) between two groups: isolated REAHs and associated REAHs. The difference between groups was considered significant if p < 0.05. (Table 3) ETHICAL CONSIDERATIONS Ethical approval was granted by the Universiti Kebangsaan Malaysia Research Ethics Committee (JEP-2025-084); patient data were anonymized and individual consent was waived.

In our center, from 2012 – 2023, out of 339 nasal biopsies, there were only 8 histopathological proven REAH. Characteristic histologic findings on hema- toxylin and eosin (H&E) staining included nests of res-piratory epithelium with a thickened basement membrane and proliferation of serous glands (Figure 1a-b). Patient demographic data are summarized in Table 1, showing an equal distribution of men (n = 4) and women (n = 4) with a mean age of 55.6 years (57.5 years for men and 53.8 years for women), ranging from 33 to 73 years. All patients experienced nasal obstruction, with two also presenting additional symptoms: one with epistaxis and the other with anosmia. Of the eight patients, three had isolated lesions, while the remaining five presented with REAH in the context of chronic sinonasal inflammatory conditions. Isolated REAHs were unilateral, whereas associated REAHs appeared both unilaterally and bilaterally. In the isolated group, two REAHs originated from the anterior and posterior septum, respectively, while one arose from the maxillary sinus. Among the cases associated with chronic rhinosinusitis, 80% were linked to nasal polyposis (n=4). Of these, three originated from the medial turbinate, one from the superior turbinate, and one from the olfactory cleft. Statistically, there was no significant association between the variables (gender, smoking history, symptom duration score, and presenting symptoms) with associated or isolated REAHs; however, this may be limited by the small sample size of the study. No patients had synchronous sinonasal tract malignancy. During nasal endoscopy, REAHs appeared as rubbery, non-friable, non-vascular polypoid masses with a darker tan color (Figure 2a-c), making them distinct from typical nasal polyps or inverted papillomas, though gross differentiation can still be challenging. Only 5 patients underwent radiological evaluation showing hypodense lesions arising from the respective sites with no surrounding bony erosion. One patient with associated REAH arising from olfactory cleft had mean olfactory clefts widening of ~20mm (Figure 3a-b). All of 8 patients underwent successful endoscopic excision of the lesion with no evidence of recurrence. TABLE 1 Patients with REAH identified from 2012-2023 in HCTM | 1 | 68 | M | 10 pack years | Nasal obstruction | 10 years | 4 | UL | Medial aspect of superior turbinate (Figure 2a-c) | CRSsNP | CT PNS Contrasted Hypodense soft tissue 2.9 x 1.6 x 3.3cm arising from left medial wall of middle turbinte, with no bony destruction. Minimal mucosal thickening of b/l frontal and ethmoidal sinuses. | Endoscopic resection (OT) | NED | | 2 | 73 | M | No | Unilateral nasal obstruction | 6 months | 2 | UL | Anterior septum | Isolated | n/a | Endoscopic resection (office) | NED | | 3 | 33 | M | Yes | Nasal obstruction | 5 months | 1 | UL | Anteroinferior wall of the maxillary sinus | Isolated | CT PNS Contrasted. Large 7.9 x 3.3 x 5.2 left sino-nasal homogenous lesion with extension to posterior nasopharynx, left ethmoid, left sphenoid, left frontal and left maxillary sinus withouy evidence of bony erosion. | Endoscopic resection with uncinectomy, MMA and medial maxillectomy. | NED | | 4 | 55 | F | No | Epistaxis with nasal obstruction | 5 months | 1 | UL | Posterior septum | Isolated | CT PNS Contrasted Non enhancing lesion 3.6 x 2.73 x 3.3cm with epicenter within the left nasal cavity | Endoscopic resection with posterior septectomy | NED | | 5 | 51 | F | No | Nasal obstruction | 1 year | 2 | BL | Olfactory clefts | CRSwNP | CT PNS (contrasted) Non enhancing (opacity) soft tissue occupying b/l olfactory clefts with no bony erosion. B/l maxillary sinusitis (Figure 3a-b) | Endoscopic resection (office) | NED | | 6 | 56 | M | No | Nasal obstruction | More than 15 yearns | 4 | UL | Lateral to medial turbinate | CRSwNP | n/a | Endoscopic resection (office) | NED | | 7 | 57 | F | No | Nasal obstruction | > 10 years | 4 | BL | Medial to medial turbinate | CRSwNP | n/a | Endoscopic resection (office) | | | 8 | 52 | F | No | Anosmia with nasal obstruction | 2 years | 2 | UL | Medial to Medial turbinate | CRSwNP | MRI base of skull and paranasal sinuses Hypointense on T1, Hyperintense on T2 soft tissue lesion 3.2 x 1.0 x 1.9cm on medial aspect of left ethmoid sinus with bilateral ethmoid sinusitis. | Endoscopic resection (office) | NED | M= male; F= female; UL = unilateral; BL = bilateral, N/A = no available, NED = no evidence of disease CRSwNP = chronic rhinosinusitis with nasal polyposis; CRSsNP = chronic rhinosinusitis without nasal polyposis TABLE 2 Symptom duration score | 5 years | 4 | TABLE 3 All patients with a pathologic diagnosis of REAH | Age, years (mean) | 56.8 | 46.3 | 1.000 | | Gender | 1.000 | || | Male | 2 | 2 | | | Female | 3 | 1 | | | Smoking history | 1 | 1 | 1.000 | | Symptoms duration score (mean) | 3.2 | 1.3 | 0.143 | | Presenting symptoms* | 0.643 | || | Nasal obstruction | 5 | 3 | | | Epistaxis | 1 | || | Anosmia | 1 | *overlapped Note: p>0.05 signifies non-significant association between variables DISCUSSIONS The term ”hamartoma” (derived from the Greek ”hamartia,” meaning ”to falter or to make an error,” and ”-oma,” indicating ”a tumor or neoplasm”) was first introduced and elucidated by a German Pathologist, Albrecht, in 1904. 2 A hamartoma is a localized abnormality that resembles a benign neoplasm, consisting of disordered but cytologically normal mature cells and tissues native to its origin. Hamartomas may arise in various parts of the body, primarily originating from the skin or subcutaneous tissue, abdominal organs; however, involvement of the head and neck is extremely rare. Consequently, such growths are seldom encountered by otolaryngologists. In this region, the commonly observed locations for hamartomas include soft tissue in the oral cavity eg: tongue, cheek area and muscular section within the neck region. 3 In the latest 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Nasal Cavity, Paranasal Sinuses and Skull Base 2022, sinonasal hamartomas are divided into respiratory epithelial adenomatoid hamartoma (REAH), seromucinous hamartoma, and nasal chondromesenchymal hamartoma (NCMH), with REAH being the most common hamartoma in the sinonanasal tract. In the previous 4h edition, there were 4 entities of hamartomas have been classified in the sinonasal tract based on their distinctive histological characteristics: respiratory epithelial adenomatoid hamartoma (REAH), seromucinous hamartoma (SMH), chondroosseous and respiratory hamartoma (CORE), and nasal chondromesenchymal hamartoma (NCMH). However, CORE has been proposed as one of the subsites of REAH, where it falls between REAH and the NCMH because it includes features of both entities, involving both epithelial and mesenchymal elements. Respiratory epithelial adenomatoid hamartoma is a prominent proliferation of glandular tissue lined by ciliated respiratory epithelium that originates from the surface epithelium. 7 It was initially documented in 1995 by Wenig and Heffner 4 and later incorporated into the World Health Organization Classification of Head and Neck Tumors in 2005. 8 In the nose and paranasal sinuses, REAH most frequently occurs at the posterior part of the nasal septum. Other common locations include the nasopharynx, frontal sinus, maxillary sinus, and ethmoid sinus. REAH is a key differential diagnosis for sinonasal masses, though it can be challenging to identify based solely on clinical or radiological features, as histological characteristics remain crucial for diagnosis. Once considered extremely rare, REAH is now recognized as more common, particularly in cases with nasal polyps. This shift may be due to increased clinician awareness and more frequent incidental findings during histopathological examination, with more cases being reported in the literature. Historically, REAH is typically characterized by a polypoid proliferation of medium-sized, branching glands extending from the surface epithelium into the stroma. These glands are separated by varying amounts of edematous stroma, often in association with chronic inflammation. The epithelium is of ciliated pseudostratified with mucinous metaplasia, resulting in mucin-dilated glands. The epithelium may appear atrophic with a flattened appearance, and the glands are usually surrounded by a thick, eosinophilic basement membrane. 4 In comparison, nasal polyps lack both glandular proliferation and surface epithelial invagination, while inverted papillomas show invagination of hyperplastic respiratory epithelium—features that are not present in REAH. A 9-year study led by Mühlmeier et al. found REAH in 1 out of 370 tissue samples from nasal surgeries, accounting for 0.27% of 8145 interventions confirming it clinical rarity. The tumor, often arising from the posterior nasal septum, can present with symptoms like epistaxis, headaches, persistent rhinorrhea, and sinusitis, with variations depending on its size and extent. 9 REAH manifests in two forms: as an independent lesion or linked to another inflammatory process, the latter often being an incidental finding. In a comprehensive study by Hawley et al., 27% of REAH cases were isolated sinonasal masses, while 73% were associated with conditions such as sinonasal polyposis, adenoiditis, hereditary hemorrhagic telangiectasia, inverted papilloma, or malignancy. For isolated REAHs, the most frequent site was the olfactory cleft (75%), followed by the middle turbinate (25%), nasal septum (16.7%), and sphenoid sinus (8.3%). 10 Bilateral REAHs (66.7%) were more common than unilateral ones, a trend also observed in most literature reviews. 11 However, in our local series, REAH was more often found to be unilateral. Irrespective of whether presented as isolated or associated lesions, endoscopic resection was curative for REAHs, aligning with outcomes from prior studies. 11 Surgical resection remains the recommended treatment, particularly for diagnostic confirmation and to prevent potential complications, such as orbital or intracranial extension. 12 The median age was 57.7 with a strong male predilection however in our study there was an equal gender distribution. Nasal obstruction, hyposmia/anosmia, headache and rhinorrhoea were the most common reported presenting complaints from literature reviews, which is consistent with our findings. 11 Preoperative imaging, particularly CT, plays a key role in identifying REAH, revealing exophytic polypoid homogeneous lesion with olfactory cleft (OC) widening without bony erosion being a characteristic finding. 7 Lima et al. first noted that patients with REAH have a mean OC width of 12.1 mm, compared to narrower OCs in those with nasal polyposis or no sinus disease. OC widening greater than 10 mm, bilateral OC masses, a size ratio between OCs <2, and absence of bony erosion are suggestive of REAH. (13,14) Although CT is the preferred modality, MRI findings indicate REAH as a homogenous, contrast-enhancing mass on T1-weighted images and hyperintense on T2-weighted images. 14 Due to the limited clinical data on REAH, primarily from case series, there are no evidence-based guidelines for the extent of surgical excision. REAH is often associated with nasal polyposis, seen in 50% of cases in a systemic review done by Safi et. Al In such cases, standard endoscopic sinus surgery (ESS) is typically performed to treat the inflammatory tissue without aggressive resection. For isolated REAH, additional surgical strategies, such as subperiosteal dissection, have been suggested, with a focus on complete but conservative excision to prevent recurrence and minimize morbidity. 14 In a cross-sectional prevalence study done by Issa et.al revealed that out of 114 patients with nasal polyposis who underwent nasal endoscopic surgeries, 54 (47.4%) had tissue with a dense and hardened polypoid aspect, a slight cerebriform appearance grossly and histologically confirmed REAH after reviewed by an experienced pathologist in the anatomopathological diagnosis of REAH. This suggests that the presence of hamartomas in polyposis is common but could underdiagnosed. 15

REAH is a benign glandular proliferation originating from the nasal cavity’s surface epithelium, with diagnosis confirmed through histopathology. It can occur in isolation or alongside other inflammatory conditions. Surgical resection is typically curative, though prospective studies on clinical outcomes and further pathological research are needed to better understand the disease and improve management. A high clinical suspicion for REAH—characterized by endoscopic findings of rubbery, non-friable, non-vascular polypoid masses with a darker tan color, and radiologic features of exophytic homogeneous lesions without bony erosion and olfactory cleft widening over 10 mm—can help prevent unnecessary or aggressive treatments.

1. Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology. 10th ed. Philadelphia: Elsevier; 2017. 2. Terris MH, Billman GF, Pransky SM. Nasal hamartoma: case report and review of the literature. Int J Pediatr Otorhinolaryngol. 1993;28:83–8. 3. Jain RK. Hamartoma of the head and neck. Indian J Otolaryngol Head Neck Surg. 2003;55:76–8. https://doi.org/10.1016/B978-0-7234-3261-6.50020-7 4. Wenig BM, Heffner DK. Respiratory epithelial adenomatoid hamartomas of the sinonasal tract and nasopharynx: a clinicopathologic study of 31 cases. Ann Otol Rhinol Laryngol. 1995;104:639–45. https://doi.org/10.1177/000348949510400809 5. Lee JT, Garg R, Brunworth J, Keschner DB, Thompson LD. Sinonasal respiratory epithelial adenomatoid hamartomas: series of 51 cases and literature review. Am J Rhinol Allergy. 2013;27:322–8. 6. Rom D, Lee M, Chandraratnam E, Chin R, Sritharan N. Respiratory epithelial adenomatoid hamartoma: an important differential of sinonasal masses. Cureus. 2018;10:e2461. 7. WHO Classification of Tumours Editorial Board. Head and Neck Tumours. 5th ed. Lyon: International Agency for Research on Cancer; 2023. (WHO Classification of Tumours series, vol. 9). https://publications.iarc.who.int/629 8. Wenig BM. Respiratory epithelial adenomatoid hamartoma. In: Barnes L, Eveson J, Reichart P, Sidransky D, editors. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005. p. 33. 9. Mühlmeier G, Hausch R, Arndt A, Kraft K, Danz B, Maier H. Respiratory epithelial adenomatoid hamartoma of the nose and nasal sinuses: a rare differential diagnosis of nasal polyposis. HNO. 2014;62:813–7. 10. Hawley KA, Pabon S, Hoschar AP, Sindwani R. The presentation and clinical significance of sinonasal respiratory epithelial adenomatoid hamartoma (REAH). Int Forum Allergy Rhinol. 2013;3:248–53. 11. Hawley KA, Ahmed M, Sindwani R. CT findings of sinonasal respiratory epithelial adenomatoid hamartoma: a closer look at the olfactory clefts. Am J Neuroradiol. 2013;34:1086–90. 12. Safi C, Li C, Tabaee A, Ramakrishna R, Riley CA. Outcomes and imaging findings of respiratory epithelial adenomatoid hamartoma: a systematic review. Int Forum Allergy Rhinol. 2019;9:674–80. 13. Issa MJ, Oliveira VR, Nunes FB, Vasconcelos LO, Souza LF, Cherobin GB, et al. Prevalence of respiratory epithelial adenomatoid hamartomas (REAH) associated with nasal polyposis: an epidemiological study—how to diagnose. Braz J Otorhinolaryngol. 2022;88(Suppl 5):57–62. Figure 1 a) Histopathological features of case 1. Low power microscopic examination (x100) showed polypoid proliferation of medium-sized, branching glands extending from the surface epithelium into the stroma b) Histopathological features of case 1. Low power microscopic examination (x100) showed respiratory mucosa overlying widely spaced medium sized glands lines by pseudostratified ciliated columnar epithelium Figure 2 1. Left sided endoscopic view of case 1 showing mass arising medial to superior turbinate 2. Left sided endoscopic view of case 1 showing mass arising medial to superior turbinate (rubbery polypoid mass with a darker tan color) 3. Gross specimen of case 1 Figure 3 Computed tomography (coronal view) of case 5 demonstrating widening of bilateral olfactory cleft Computed tomography (axial view) of case 5 demonstrating widening of bilateral olfactory cleft Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Metrics & Citations Metrics Article Usage 332views 138downloads Citations Download citation Noor Shairah Mat Barhan, Nadhirah Mohd Shakri, Isa Mohamed Rose, et al. RESPIRATORY EPITHELIAL ADENOMATOID HAMARTOMA (REAH): UNCOMMON NASAL POLYPS MASQUERADER - EVALUATION AT HOSPITAL CHANCELLOR TUANKU MUHRIZ, MALAYSIA. Authorea. 16 October 2025. DOI: https://doi.org/10.22541/au.176061635.59187391/v1 DOI: https://doi.org/10.22541/au.176061635.59187391/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.