Fat-Containing Minor Salivary Gland Proliferation of the Supraglottis: Challenging the “Ectopic” Paradigm

Introduction

Heterotopic salivary gland tissue (also referred to as ectopic salivary gland tissue or salivary gland choristoma) is defined as histologically normal salivary gland tissue occurring outside the usual anatomical distribution of the major and minor salivary glands. ¹ Although this concept is well established, the pathogenesis of such lesions remains uncertain, and proposed mechanisms include aberrant embryological displacement of salivary gland primordia or abnormal differentiation of local epithelial elements capable of salivary gland formation.^2,3 Ectopic salivary gland tissue has been reported at various sites within the head and neck, most commonly in the cervical region and lymph nodes.^1,4 Less frequently, it has been described in the middle ear, tonsil, tongue, and mandible.^5,6

Although laryngeal involvement is distinctly uncommon, the reported lesions exhibit a remarkably consistent anatomical and histomorphological pattern. Most arise within the supraglottic larynx, where minor salivary glands are normally distributed, and are characterized by seromucous glandular elements intimately associated with mature adipose tissue, often accompanied by lymphoid aggregates. This characteristic anatomical distribution raises questions regarding whether such lesions truly represent developmental heterotopia.

The classification of these lesions remains controversial. In addition to heterotopic and choristomatous designations, some morphologically similar laryngeal lesions have been interpreted as hamartomas.^7,8 Choristoma is defined as histologically normal tissue occurring in an abnormal location, whereas hamartoma represents a disorganized overgrowth of indigenous tissues at their normal anatomical site. ⁹ Nevertheless, the boundaries between these diagnostic categories remain ill-defined, and the terminology applied in the literature has not always been accompanied by clear anatomical or pathogenetic justification. The recurring association of native glandular elements, adipose tissue, and reactive stromal changes suggests that at least some reported lesions may not fit neatly within traditional concepts of either heterotopia or hamartoma.

Oncocytic metaplasia of salivary gland epithelium is a well-recognized age-related phenomenon, frequently associated with chronic inflammation and well-documented throughout the upper aerodigestive tract, including the larynx.^10–12 Laryngeal oncocytic cysts are uncommon benign lesions that show a strong association with cigarette smoking.^10–13 Oncocytic change is generally regarded as a metaplastic rather than a neoplastic process, resulting from age-related cellular exhaustion, chronic mucosal injury, and compensatory mitochondrial proliferation.^10,12 When accompanied by lymphoid tissue, it may create a superficial resemblance to Warthin tumor, a benign salivary gland neoplasm that is likewise strongly associated with smoking. ¹³ The presence of such changes in the present lesion broadens the morphological spectrum of these lesions and adds an additional layer of diagnostic complexity.

In this report, we describe a supraglottic fat-containing minor salivary gland proliferation associated with oncocytic cystic change and a reactive lymphoid aggregate. In the context of previously reported laryngeal lesions, we critically reexamine the traditional heterotopic interpretation of these lesions and explore whether at least a subset may be more appropriately regarded as localized adenolipomatous proliferations of native minor salivary glands.

Case Report

A 63-year-old man presented with persistent throat discomfort of 4 months’ duration. He had no significant past medical history. He was a former smoker with a 40-pack-year history and had ceased smoking 2 years earlier. Flexible laryngoscopy revealed a nodular lesion in the left supraglottic region; an initial biopsy was nondiagnostic. Computed tomography confirmed a well-defined 9.5 × 6.5 mm left supraglottic nodule adjacent to the laryngeal ventricle (Figure 1).

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Figure 1.

Axial computed tomography of the larynx demonstrating a well-defined nodule in the left supraglottic region measuring approximately 9.5 × 6.5 mm (arrows).

Direct microlaryngoscopy demonstrated a lesion involving the ventricular band and extending toward the laryngeal ventricle, in close proximity to, but not involving, the true vocal cord. A separate 3-mm cystic component was identified between the ventricular band and the vocal cord; its fluid contents were aspirated, and the entire nodular lesion was excised microsurgically. In addition, a subtle mucosal elevation was noted in the contralateral ventricular band region, although it lacked a discrete nodular configuration and was not biopsied.

The resected specimen measured 10 × 7 × 7 mm and consisted of a mucosa-covered polypoid lesion. Histopathological examination revealed respiratory-type epithelium with focal immature squamous metaplasia overlying a well-circumscribed but unencapsulated lobulated proliferation of mature seromucous acini intimately admixed with mature adipose tissue (Figures 2-4). The glandular component displayed a preserved lobular architecture and showed no cytological atypia or mitotic activity. Focally, cystically dilated ductal structures exhibiting oncocytic metaplasia were identified, some of which were associated with prominent lymphoid stroma (Figures 5-7). One partially denuded cystic structure lined by eosinophilic columnar epithelium was interpreted as corresponding to the previously aspirated cystic component (Figure 6). Scattered entrapped microglands and additional ductal structures showing atrophic-cystic change were present within a fibrosclerotic stroma adjacent to the main proliferation (Figures 5 and 8). The overall features were those of a well-circumscribed but unencapsulated fat-containing minor salivary gland proliferation associated with focal oncocytic cystic change and a reactive lymphoid aggregate.

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Figure 2.

Beneath respiratory epithelium showing immature squamous metaplasia, a lobulated proliferation of mature seromucous glands admixed with adipose tissue (H&E, ×40).

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Figure 3.

Seromucous acini with a hyperplastic appearance intermingled with mature adipose tissue, maintaining a well-organized lobular architecture (H&E, ×100).

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Figure 4.

Mature seromucous glands embedded within a lipomatous stroma (H&E, ×200).

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Figure 5.

Oncocytic metaplasia involving cystically dilated ductal structures, one of which is embedded within a lymphoid stroma, together with scattered entrapped microglands within the surrounding stroma (arc arrow) (H&E, ×40).

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Figure 6.

Partially denuded cystic structure lined by eosinophilic columnar epithelium and surrounded by lymphoid stroma (H&E, ×40).

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Figure 7.

Cystically dilated gland lined by epithelium showing oncocytic metaplasia (arc arrow) and surrounded by prominent lymphoid stroma (H&E, ×100).

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Figure 8.

Seromucous glands are embedded within a fibrosclerotic stroma containing scattered ductal structures, some exhibiting atrophic-cystic change (H&E, ×40).

The postoperative course was uneventful. Given the limited data regarding the biological behavior of these lesions and occasional reports of metachronous involvement, regular laryngoscopic surveillance is planned for at least 2 years.

Discussion

The pathogenesis of salivary gland tissue identified outside the major and minor salivary gland distribution remains a subject of debate. While developmental mechanisms such as aberrant embryological displacement have been proposed for lesions in locations such as the middle ear and mandible, their applicability to laryngeal lesions is less clear.^5,6

In the larynx, only 9 patients have been previously documented (Table 1).^7–13 Notably, the majority arose in the supraglottic region—an area that normally contains native minor seromucous glands—and affected middle-aged to elderly adults. This age distribution is difficult to reconcile with a purely developmental origin and suggests that acquired, possibly metaplastic or hyperplastic mechanisms may be involved. The age of the patient described herein is consistent with this demographic pattern and further supports reexamination of the histogenesis of these uncommon lesions.

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Table 1.

Clinicopathological Features of Previously Reported Patients With Laryngeal Salivary Gland Choristoma/Ectopia and Comparison With the Current Patient.

Author (year)	Age/Sex	Site	Symptom	Size (mm)	Histological features	Follow-up
Kruk-Zagajewska et al (1999)7	56/Male	Ventricle	Hoarseness	NR	Seromucous glands	NR
Kempf and Störkel (2005)5	80/Male	Vocal cord	Hoarseness	NR	Seromucous glands + adipose tissue	NR
Yılmaz et al (2017)8	43/Male	Vocal cord	Hoarseness	5	Seromucous glands + adipose tissue	NR
Tajima et al (2018)9	46/Male	False vocal cord	Throat discomfort	10	Seromucous glands + adipose tissue	NR
Valentino et al (2020)10	56/Male	False vocal cord	Hoarseness	NR	Seromucous glands	NR
Sleurs et al (2021)11	54/Male	Ventricle	Dysphonia, globus	NR	Seromucous glands	NR
Bidaye et al (2021)12 Patient 1	45/Female	False vocal cord	Dysphonia	NR	Seromucous glands + adipose tissue + lymphoid tissue	Contralateral lesion (2 years)
Bidaye et al (2021)12 Patient 2	50/Male	False vocal cord	Dysphonia	NR	Seromucous glands + adipose tissue + lymphoid tissue	NR
Tajima et al (2024)13	78/Male	Vocal cord	Hoarseness	NR	Seromucous glands	NR
Current patient	63/Male	Ventricular band/ventricle	Throat irritation	9.5 × 6.5	Seromucous glands + adipose tissue + lymphoid aggregate + oncocytic cyst	NED (3 months)

a

Abbreviations: NR, not reported; NED, no evidence of disease.

A notable finding emerging from the literature review is the remarkable morphological consistency among previously reported examples. Although individual authors have used different diagnostic designations, the majority share a common histological pattern characterized by benign seromucous glandular elements intimately admixed with mature adipose tissue. Kempf and Störkel described heterotopic salivary gland tissue located within muscle and fat; however, the published photomicrographs do not unequivocally demonstrate skeletal muscle, leaving uncertainty regarding true intramuscular localization.⁵ Similarly, the lesion illustrated by Yılmaz et al shows mature adipose tissue closely associated with seromucous acini, ⁸ while the patients reported by Bidaye et al demonstrate a comparable admixture accompanied by prominent lymphoid tissue. ¹² Tajima et al reported a macroscopically yellow mass, a finding that is highly suggestive of a substantial adipose component. ⁹ Collectively, these observations suggest that adipose-rich salivary gland proliferations represent a recurring morphologic pattern in the larynx.

Although adipose tissue may be encountered in normal salivary glands, particularly in the parotid gland, the prominent adipose component observed in the present lesion is unlikely to represent incidental age-related fatty replacement alone. Increased adipose infiltration has been documented in a variety of salivary gland disorders, including obesity, diabetes mellitus, chronic alcoholism, xerostomia, and Sjögren syndrome, indicating that adipose accumulation may accompany diverse forms of glandular dysfunction.^14,15 Studies of salivary gland sialosis have shown that adipose infiltration may coexist with ductal hyperplasia and acinar alterations, suggesting a close relationship between epithelial and adipocytic change. In the current specimen, the intimate admixture of mature adipose tissue with proliferating seromucous glands, together with stromal fibrosis, focal atrophic-cystic glandular change, and regenerative glandular proliferations, points toward a coordinated alteration involving multiple components of the gland rather than isolated fatty replacement.

This architectural pattern bears resemblance to the spectrum of fat-containing salivary gland lesions described in the major salivary glands. Agaimy classified these lesions into true adipocytic neoplasms and mixed lipoepithelial proliferations composed of salivary gland elements and mature adipose tissue, including sialolipoma and lipoadenoma. ¹⁶ However, unlike these well-circumscribed salivary gland tumors, the present lesion lacked a discrete mass-forming architecture and instead demonstrated a diffuse admixture of seromucous glands and adipose tissue. As emphasized by Tsaprazlis et al in the differential diagnosis of adipose-rich salivary gland lesions, there was no evidence of chondromyxoid stromal differentiation or epithelial–myoepithelial proliferation to suggest pleomorphic adenoma with lipometaplasia. ¹⁷

A hamartomatous interpretation has been applied to several morphologically similar laryngeal lesions. However, a critical review of the available literature suggests considerable heterogeneity among lesions classified under this designation. Oweidat et al identified fewer than 35 reported patients with laryngeal hamartoma, approximately two-thirds of whom were pediatric patients, with a bimodal age distribution showing peaks in early childhood and later adulthood. ¹⁸ Pediatric lesions more closely align with the classical concept of hamartoma, often demonstrating mesenchymal diversity in addition to native laryngeal tissues. Examples include the neonatal hamartomas reported by Gonjari et al, Uçar et al, and Dani et al, which contained cartilage and/or smooth muscle in addition to native laryngeal components.^19–21

In contrast, many adult lesions reported as laryngeal hamartomas are composed predominantly of mature native supraglottic elements, including seromucous glands, adipose tissue, lymphoid tissue, and vascular structures. The hamartomas reported by Higo et al and Veselski Krajinović et al, together with the lesion described in the adult patient reported by Oweidat et al, lacked the mesenchymal diversity characteristic of congenital hamartomatous malformations.^18,22,23 Furthermore, their occurrence in adults contrasts with the congenital presentation typical of true laryngeal hamartomas and may favor an acquired rather than developmental process.

The glandular component provides additional insight into the nature of this proliferation. The prominent seromucinous glandular expansion resembles adenomatoid hyperplasia of minor salivary glands, a condition characterized by enlargement of otherwise unremarkable glandular elements. Barrett and Speight reported a high prevalence of tobacco use among affected patients and proposed chronic local irritation as a possible etiological factor. ²⁴ The combination of glandular expansion, stromal fibrosis, focal atrophic-cystic change, and regenerative-appearing glandular proliferations suggests an ongoing process of tissue remodeling. Viewed in this context, the overall morphological profile is more consistent with adenomatoid hyperplasia than with either heterotopia or hamartoma.

The lymphoid aggregate containing an oncocytic epithelial-lined cyst creates a superficial resemblance to Warthin tumor, a benign salivary gland neoplasm characterized by bilayered oncocytic epithelium supported by prominent lymphoid stroma. ¹² However, the cyst was small (3 mm), lacked the characteristic bilayered oncocytic epithelium and papillary infoldings of conventional Warthin tumor, and occurred within a nonencapsulated proliferation without evidence of expansile growth. The presence of glandular inclusions within the lymphoid aggregate raises consideration of a lymphoepithelial cyst; however, despite partial overlap with proposed mechanisms such as epithelial entrapment within lymphoid tissue and ductal obstruction,^25–27 the absence of a conventional squamous-lined keratinizing cyst argues against that interpretation. The deep supraglottic location may further account for the lack of squamous differentiation and keratinization typically encountered in superficial lymphoepithelial cysts. Accordingly, the cystic component is most consistent with retention-type cyst formation accompanied by focal oncocytic metaplasia.

Chronic tobacco exposure has been associated with persistent epithelial injury, oxidative stress, and inflammatory change within the upper aerodigestive tract, while reactive lymphoid aggregates may arise within the supraglottic compartment, where laryngeal-associated lymphoid tissue is normally present. ²⁸ Oncocytic metaplasia is also a well-recognized age-related alteration of laryngeal seromucous glands. Yamase and Putman observed oncocytic transformation in the majority of larynges from individuals older than 50 years, whereas such changes were absent in younger subjects. ²⁹ Similarly, Salerno et al noted that laryngeal oncocytic cysts occur predominantly in elderly patients and represent a characteristic alteration of aging seromucous glands. ³⁰

The biological behavior of these lesions remains poorly defined because of their rarity and the limited duration of follow-up reported in the literature. Bidaye et al documented the development of a metachronous lesion in the contralateral false vocal cord 2 years after excision of the original lesion. ¹² Similarly, the patient described herein demonstrated a subtle contralateral mucosal prominence within the ventricular band region at presentation, although no discrete lesion was identified. Although these observations are insufficient to establish a definitive pattern of multifocality, they raise the possibility that the supraglottic minor salivary gland compartment may be susceptible to localized proliferative changes affecting multiple sites over time.

The patient remains free of symptoms and disease progression at 3 months of follow-up. Given the limited understanding of the natural history of these lesions and occasional reports of metachronous involvement, periodic endoscopic surveillance appears reasonable. Longer follow-up and additional observations are needed to better define their biological behavior and classification.

Conclusions

The recurrent association of native seromucous glands, adipose tissue, and reactive stromal changes in predominantly adult-onset lesions challenges their traditional classification as either heterotopia or hamartoma. Their consistent occurrence within gland-bearing supraglottic mucosa and the frequent absence of architectural disorganization or heterologous mesenchymal elements suggest that many reported examples may instead represent localized proliferations of native minor salivary glands. Within this framework, accompanying oncocytic and lymphoid changes are best regarded as secondary reactive phenomena. For nonencapsulated lesions lacking evidence of autonomous growth, terms such as adenolipomatous hyperplasia or fat-containing salivary gland hyperplasia may more accurately reflect their morphology and pathogenesis.