A case of adenoid cystic carcinoma of the larynx: Diagnostic challenges, surgical management, and long-term surveillance

Abstract

Adenoid cystic carcinoma of the larynx is an uncommon malignant neoplasm, accounting for less than 1% of all laryngeal cancers. It arises from minor salivary glands, predominantly located in the subglottic region. ACC is characterized by slow but aggressive growth, with a notable propensity for perineural invasion and distant hematogenous dissemination, particularly to the lungs, which occurs in approximately 35%-50% of cases. Clinical presentation depends on tumor localization and may include dyspnea, dysphonia, dysphagia, and otalgia. Diagnosis is based on clinical and endoscopic examination, supplemented by imaging modalities such as MRI and CT scans, and confirmed by histopathological evaluation, which typically reveals a cribriform growth pattern. Immunohistochemical analysis frequently shows strong positivity for c-kit (CD117) and CK7, with negative expression for thyroid-specific markers (TTF-1, thyroglobulin), excluding a thyroid origin. The standard therapeutic approach involves wide surgical excision, most often via total laryngectomy, with selective neck dissection performed in cases with clinical or radiological evidence of lymph node involvement, although nodal metastases remain uncommon. Postoperative radiotherapy is generally indicated due to the tumor’s relative radioresistance and its tendency for perineural spread. Chemotherapy plays a limited role, reserved for advanced or metastatic disease. Given the high risk of late recurrences and distant metastases, long-term follow-up is essential, despite a reported 5-year overall survival rate of approximately 70%. We report the case of a 58-year-old female patient with no history of tobacco or alcohol use, but with a 25-year occupational exposure to irritant vapors in the chemical industry. She presented with progressively worsening dysphonia over approximately 10 months, followed by the onset of laryngeal dyspnea. A comprehensive clinical evaluation, supported by laboratory testing and imaging studies, led to the diagnosis of adenoid cystic carcinoma of the larynx. This exceedingly rare tumor may present with nonspecific symptoms and mimic other head and neck disorders, particularly thyroid-related pathologies. Therefore, a high index of clinical suspicion is essential to avoid diagnostic delays. Early diagnosis and prompt management are critical, and treatment should be based on a multidisciplinary and individualized approach to optimize oncological outcomes while preserving laryngeal function and the patient's quality of life.

Introduction

Adenoid cystic carcinoma (ACC) is a malignant epithelial tumor typically observed in the major and minor salivary glands. Its occurrence in the larynx is exceedingly rare, accounting for less than 1% of all laryngeal malignancies. This rarity is attributed to the low density of accessory salivary glands in the laryngeal region, particularly in the glottic and supraglottic areas. Nevertheless, ACC can originate from subepithelial glands, most commonly in the subglottic region, and present as submucosal masses that are often challenging to detect both clinically and radiologically [1].

Epidemiologically, laryngeal ACC demonstrates a slight female predominance and typically affects individuals in their fifth and sixth decades of life. Although it progresses slowly, the tumor is locally aggressive, with a notable tendency for perineural invasion and hematogenous spread. Cervical lymph node involvement is uncommon, occurring in approximately 10%-15% of cases. Conversely, direct extension to adjacent structures such as the thyroid gland, though infrequent, may mimic primary thyroid pathology and delay accurate diagnosis.

The positive diagnosis of ACC requires a multimodal approach. Clinically, symptoms are often nonspecific and insidious, including hoarseness, progressive dyspnea, pharyngeal discomfort, or the presence of a neck mass. Laryngoscopic examination may reveal a submucosal endophytic lesion, while magnetic resonance imaging (MRI) provides a detailed assessment of local tumor extension, although it may underestimate subclinical spread. Definitive diagnosis is based on histopathological analysis of biopsy specimens, revealing characteristic cribriform, tubular, or solid architectural patterns. Immunohistochemistry is crucial in differentiating ACC from thyroid neoplasms, showing positivity for CD117 (C-kit), CK7, S-100, and P63, and negativity for thyroglobulin and TTF-1 in cases of secondary thyroid invasion [2].

Management is primarily surgical, with wide local excision, most often via total laryngectomy, being the treatment of choice. Partial laryngectomy may be considered in selected cases with well-defined, limited disease and clear resection margins. In the absence of clinically or radiologically suspected lymph node metastasis, elective neck dissection is generally not recommended. Postoperative radiotherapy may be indicated in cases of positive margins or advanced local disease, although its impact on overall survival remains inconclusive [3].

Case presentation

We report the case of a 58-year-old female patient with no personal history of tobacco use or alcohol consumption. However, she had a significant occupational exposure, having worked for 25 years in a chemical manufacturing industry where she was chronically exposed to industrial irritant vapors.

She presented with progressively worsening dysphonia evolving over approximately ten months, initially isolated. The clinical course was subsequently complicated by the onset of inspiratory dyspnea suggestive of a laryngeal origin, first occurring on exertion and later at rest, without associated dysphagia, otalgia, or cervical pain.

The symptomatology was accompanied by a general decline in health status, characterized by marked fatigue (asthenia) and progressive, clinically significant weight loss of unquantified extent. No fever or night sweats were reported.

Initial clinical examination revealed a hoarse, breathy, and asthenic voice. Cervical palpation did not reveal any palpable masses or cervical lymphadenopathy. Flexible nasofibroscopy demonstrated a submucosal mass located on the laryngeal surface of the epiglottis, extending to the left aryepiglottic fold. Complete immobility of the left vocal cord was observed, along with a slight reduction in mobility of the left hemilarynx. The right vocal cord appeared uninvolved (Fig. 1).

Fig. 1.

Figure showing a nasofibroscopic image depicting a submucosal mass located on the laryngeal surface of the epiglottis, extending to the left aryepiglottic fold. Complete immobility of the left vocal cord was observed, along with slight reduction in mobility of the left hemilarynx. The right vocal cord appeared unaffected.

Initial laboratory work-up revealed a moderate normochromic normocytic anemia (hemoglobin: 11.2 g/dL), with no leukocytosis or thrombocytopenia. There was no evidence of systemic inflammation (CRP <5 mg/L; ESR: 12 mm at the first hour). Renal function (creatinine: 68 µmol/L) and liver function tests (AST, ALT, ALP, total and conjugated bilirubin) were within normal limits. Thyroid function (TSH) and serum electrolytes were unremarkable. Viral serologies for HIV, hepatitis B, and hepatitis C were negative. These findings supported the absence of any contraindication to major surgical intervention.

The contrast-enhanced cervico-thoracic computed tomography (CT) revealed a hypodense lesion located supraglottically, centered on the cricoid cartilage and arytenoids, with irregular borders and extension into surrounding structures, particularly the epiglottis and aryepiglottic fold. The mass appears to infiltrate adjacent soft tissues, showing heterogeneous contrast enhancement, suggesting an infiltrative tumor process. The larynx shows asymmetry with partial glottic stenosis due to narrowing of the airway at the tumor site. No cervical lymphadenopathy or mediastinal metastases were detected. Other laryngeal cartilages remain relatively spared, although there is significant invasion of the soft tissues on the posterior laryngeal wall (Fig. 2, Fig. 3).

Fig. 2.

Figure showing an axial CT scan image of a hypodense lesion located in the supraglottic region, centered on the cricoid cartilage and arytenoids, with irregular borders and extension into surrounding structures, particularly the epiglottis and aryepiglottic fold.

Fig. 3.

Figure showing a coronal CT scan section depicting a hypodense lesion located in the supraglottic region, centered around the cricoid cartilage and arytenoids. The lesion presents with irregular borders and demonstrates extension into adjacent structures, including the epiglottis and aryepiglottic fold.

In light of the clinical presentation, endoscopic findings, and radiologic data, the case was reviewed in a multidisciplinary tumor board (MDT). The consensus recommendation was to proceed with direct laryngoscopy under general anesthesia and multiple biopsies of the supraglottic mass.

Histopathological analysis of the biopsy specimens confirmed the diagnosis of ACC of the larynx, a rare malignancy known for its indolent progression but significant perineural invasion potential (Fig. 4).

Fig. 4.

Histopathological examination of the laryngeal tumor demonstrating features of adenoid cystic carcinoma. The tumor exhibits a characteristic cribriform growth pattern composed of basaloid epithelial cells forming pseudocystic spaces filled with hyaline material, along with perineural invasion. Hematoxylin and eosin (H&E) staining, original magnification ×200.

Given the tumor location, histologic subtype, and local extension, a total laryngectomy was indicated and successfully performed (Fig. 5).

Fig. 5.

Figure showing the operative specimen from a laryngectomy, depicting the excised laryngeal tissue.

Postoperative recovery was uneventful. A nasogastric feeding tube was maintained for 10 days to minimize the risk of pharyngocutaneous fistula formation. Prophylactic antibiotic therapy with cefazolin (1 g every 8 hours) was administered for 7 days, along with proton pump inhibitor therapy throughout hospitalization. Closed-suction drains (Redon) were removed 78 hours postoperatively.

The patient has been followed regularly in a specialized ENT clinic, with quarterly clinical assessments during the first 2 postoperative years. To date, there has been no evidence of local or regional recurrence, either clinically or radiologically.

Discussion

ACC of the larynx is an exceptionally rare malignant neoplasm, arising from the minor salivary glands embedded within the submucosa of the laryngeal tract. Although it accounts for less than 1% of all laryngeal malignancies, its clinical significance lies in its unique biological behavior. ACC is notorious for its indolent yet relentless growth, high rate of local recurrence, pronounced perineural invasion, and late-onset hematogenous metastases, particularly to the lungs. Its atypical presentation, often with subtle or nonspecific symptoms, contributes to diagnostic delays and complex therapeutic management, distinguishing it from the more prevalent squamous cell carcinomas of the larynx [4].

The incidence of laryngeal ACC is estimated to range between 0.07% and 0.25% of all laryngeal tumors. It most commonly affects individuals between the ages of 50 and 70 years, with a slight male predominance (male-to-female ratio approximately 1.5:1). The distribution of lesions correlates with the anatomical density of minor salivary glands within the larynx. The subglottic region is most frequently involved (approximately 60% of cases), followed by the supraglottic area (25%), the glottis (5%), and transglottic locations (6%). This anatomical predilection influences not only clinical presentation but also the approach to diagnosis and treatment.

One of the hallmark features of ACC is its strong neurotropic behavior. Perineural invasion is observed in nearly two-thirds of cases, contributing to local aggressiveness and a high risk of recurrence, even in the setting of seemingly adequate surgical margins. Conversely, lymphatic dissemination is uncommon, with cervical lymph node involvement reported in only 10%-20% of cases. Distant metastases, however, particularly pulmonary, occur in approximately 35%-50% of patients and may emerge several years after initial treatment, underscoring the importance of long-term surveillance [5].

At the molecular level, several genetic and protein expression abnormalities have been implicated in ACC pathogenesis. Overexpression of c-KIT (CD117), a tyrosine kinase receptor, is consistently observed and is thought to contribute to tumor proliferation and survival via the activation of intracellular signaling pathways, such as PI3K/AKT and RAS/RAF/MEK. In addition, the recurrent chromosomal translocation t(6;9)(q22–23;p23–24), resulting in the MYB-NFIB fusion gene, has been identified as a pivotal molecular event in ACC tumorigenesis. This translocation leads to aberrant MYB transcription factor activation, which promotes oncogenic gene expression programs. These molecular insights offer potential avenues for the development of targeted therapies and novel biomarkers [6].

The positive diagnosis of laryngeal adenoid cystic carcinoma (LACC) relies on a comprehensive approach combining clinical evaluation, endoscopic assessment, advanced imaging techniques, and confirmatory histopathological analysis. LACC is an exceedingly rare malignancy, accounting for less than 1% of all laryngeal tumors and approximately 10% of minor salivary gland malignancies. It arises from minor salivary glands embedded within the submucosa of the larynx, with a clear predilection for the subglottic region in 56%-64% of reported cases, followed by the supraglottic (25%-30%), glottic (5%-6%), and transglottic areas (approximately 6%) [7].

Clinically, LACC is characterized by its indolent course and non-specific symptomatology, often resulting in a significant diagnostic delay, with symptom duration prior to diagnosis frequently exceeding 8-12 months. The most common presenting complaint is progressive dyspnea, typically associated with subglottic obstruction, followed by hoarseness, dysphagia, and throat discomfort. Otalgia may occur in cases of perineural invasion. Importantly, unlike squamous cell carcinoma of the larynx, LACC does not have a known association with tobacco or alcohol exposure. It typically affects middle-aged to older adults (aged 50-70), with a slight female predominance reported in some series [8].

Endoscopic findings may be subtle due to the submucosal and infiltrative nature of the tumor. The lesion often presents as a bulging or infiltrative mass with intact overlying mucosa. Therefore, in cases of clinical suspicion with unremarkable surface findings, direct laryngoscopy under general anesthesia with deep mucosal biopsies is often required to obtain a definitive diagnosis.

Imaging studies are crucial for assessing local extension and detecting distant disease. Magnetic resonance imaging (MRI) is the preferred modality for local evaluation, revealing a poorly demarcated, heterogeneous submucosal mass with variable contrast enhancement. However, MRI may underestimate tumor extent due to its tendency for submucosal and perineural spread. CT of the neck and chest, or positron emission tomography (PET-CT), is recommended to detect regional invasion and distant metastases—most frequently involving the lungs, occurring in 30%-50% of patients, sometimes years after initial treatment [9].

Histopathological examination is central to the diagnosis. LACC exhibits a biphasic myoepithelial and ductal cell architecture, with 3 recognized histological subtypes: cribriform (most frequent), tubular (associated with a favorable prognosis), and solid (indicative of aggressive behavior). The hallmark cribriform pattern features basaloid epithelial nests with pseudocystic spaces filled with hyaline material. Perineural invasion, a hallmark of LACC, is observed in up to 65%-70% of cases, correlating with local recurrence and pain symptoms. Immunohistochemically, tumor cells commonly express CD117 (c-Kit), p63, calponin, smooth muscle actin (SMA), and occasionally S100, reflecting their myoepithelial differentiation [10].

The differential diagnosis includes several entities:

• •Mucoepidermoid carcinoma, which displays mucin-producing cells and a more heterogeneous cytological profile.
• •Neuroendocrine carcinomas, such as small cell carcinoma, distinguishable by the expression of neuroendocrine markers (chromogranin, synaptophysin, NSE).
• •Adenosquamous carcinoma, which exhibits both glandular and squamous components.
• •Chondrosarcoma, particularly in the subglottic region, may mimic LACC but contains atypical cartilaginous cells and calcified matrix.
• •Metastatic adenocarcinomas from distant primaries (eg, lung, gastrointestinal tract) should also be excluded via systemic workup.
• •Lymphomas, which may present as submucosal masses, but demonstrate lymphoid markers (CD20, CD3) on immunostaining.

Management of ACC of the larynx requires a multidisciplinary approach due to its complex behavior, including high rates of local recurrence and distant metastasis. Surgical resection remains the cornerstone of treatment, with the goal of achieving clear margins. Due to perineural invasion, complete resection can be challenging, and positive surgical margins are often associated with a higher risk of recurrence. Adjuvant radiotherapy is frequently recommended, especially in cases with close or positive margins, to control local recurrence. In cases of unresectable tumors or for patients opting out of surgery, radiotherapy can be used as the primary treatment modality.

Chemotherapy has a limited role in ACC, particularly in the early stages. However, it may be considered for advanced or metastatic disease, especially for pulmonary metastases. Agents such as cisplatin may be used in combination with radiation in select cases. Targeted therapies, particularly those targeting c-KIT overexpression and MYB-NFIB fusion, offer promising options for advanced or recurrent cases, though their efficacy is still under clinical investigation.

Finally, due to the high risk of recurrence and late pulmonary metastasis, long-term surveillance is crucial. Regular imaging (CT, MRI) is necessary to detect recurrence or metastasis, and follow-up should extend for several years post-treatment. Management of laryngeal ACC thus combines surgery, radiotherapy, long-term monitoring, and emerging targeted therapies for advanced cases [11].

Conclusion

ACC of the larynx, although rare, presents significant clinical challenges due to its indolent growth, high recurrence rate, and propensity for perineural invasion and late metastasis, particularly to the lungs. It typically presents with subtle, delayed symptoms like dyspnea and hoarseness. Diagnosis relies on a combination of endoscopy, imaging, and histopathology, with the cribriform pattern and perineural invasion being key features. While lymphatic spread is uncommon, distant metastases are frequent, highlighting the need for long-term monitoring. Molecular findings, such as c-KIT overexpression and MYB-NFIB fusion, offer promising targets for future therapies.

Patient consent for publication

The patient gave their informed consent to the publication of this case report.

Patient consent

The patient has provided informed consent for the publication of this case report.