Multifocal Laryngotracheal Rosai–Dorfman Disease: 48‐Month Remission After Surgical Resection

Abstract

A rare case of multifocal subglottic‐tracheal Rosai–Dorfman disease (RDD) achieved sustained 48‐month remission through surgical resection alone, without adjuvant therapy. This outcome suggests that surgery alone may serve as a viable alternative for select cases of multifocal airway RDD characterized by completely resectable lesions, no systemic involvement, and favorable anatomical accessibility.

1. Introduction

Rosai–Dorfman disease (RDD), classified as a clonal histiocytic neoplasm in the 5th edition of the WHO Classification of Hematolymphoid Tumors (2022) [1], was first characterized by Destombes in 1965 and defined by Rosai and Dorfman in 1969. Subglottic‐tracheal RDD is exceptionally rare, often presenting with life‐threatening airway obstruction [2]. Current guidelines favor systemic therapy (corticosteroids, immunomodulators) for multifocal disease, reserving surgery exclusively for localized lesions [3]. Herein, we report the first case of multifocal subglottic‐tracheal RDD achieving sustained 48‐month remission through curative resection alone, suggesting that surgery alone may be a viable alternative for select complex airway RDD cases with resectable lesions.

2. Case Report

A 57‐year‐old woman presented with recurrent dyspnea of 1‐month duration, occurring 24 months after T‐tube placement for idiopathic tracheal stenosis. Twelve months after T‐tube placement, the patient underwent resection for recurrent stenosis, with postoperative symptom relief but nondiagnostic pathology. However, 1 month prior to admission, she developed recurrent wheezing with progressive dyspnea, partially responsive to nebulized corticosteroids. Flexible laryngoscopy and bronchoscopy revealed recurrent tracheal stenosis: a large subglottic mass and an irregular elevated obstructive lesion (approximately 10 mm in diameter) at the bronchial inlet (Figure 1A,E). The final diagnoses included dyspnea, recurrent tracheal stenosis, and multilevel airway obstruction (subglottic and bronchial involvement). A laryngo‐thoracic contrast‐enhanced CT scan showed an endotracheal tube (mildly right‐deviated) with intraluminal soft tissue density; a 26 × 20 mm subglottic mass obstructed the airway, extending superiorly to cause bilateral vocal cord thickening and glottic stenosis, and inferiorly involving the trachea and main bronchi (with wall thickening), with a 10 × 11 mm nodule at the carina (Figure 2). Following a multidisciplinary evaluation confirming surgical eligibility, the patient underwent tracheostomy, laryngotracheal mass resection, and T‐tube placement under general anesthesia (Figure 1B,F). A longitudinal tracheal incision was made, extending from the inferior cricoid cartilage margin to the prior T‐tube stoma. Complete resection of the subglottic lesions was performed, alongside bronchoscopically assisted excision of the distal tracheal mass at the bronchial inlet. Airway reconstruction was stabilized with a new T‐tube. Postoperatively, the patient received standardized nebulization therapy, prophylactic antibiotics, and nutritional support, and was discharged on postoperative day 3. Histopathological analysis demonstrated fibrogranulation tissue proliferation with mixed acute and chronic inflammatory infiltrates, marked focal histiocytic hyperplasia, and emperipolesis (lymphocyte engulfment by histiocytes, Figure 3). Immunohistochemical staining showed S‐100 positivity, CD68 positivity, and CD1a negativity, consistent with the diagnosis of RDD. The T‐tube was removed 6 months postoperatively, with no additional therapeutic interventions administered (Figure 1C,G). A structured endoscopic surveillance protocol was implemented, combining both laryngoscopy and bronchoscopy. Examinations were performed at 1, 3, and 6 months postoperatively, and annually thereafter for a total of 48 months. At each evaluation, airway patency was thoroughly assessed. The subglottic and tracheal diameters were measured using a calibrated endoscope, and restenosis was graded as 0 (no stenosis) according to the modified Cotton‐Meyer classification. High‐resolution photographic documentation was obtained at all time points. Serial surveillance confirmed sustained, complete airway patency at all previously involved sites, with no evidence of restenosis or recurrence (Figure 1D,H). Postoperatively, the patient's dyspnea and wheezing resolved completely, and she experienced no hoarseness, dysphagia, or other procedure‐related complications. Throughout follow‐up, she regained her premorbid level of daily activity and reported no airway discomfort.

FIGURE 1.

Bronchoscopy and flexible laryngoscopy findings. (A) Preoperative bronchoscopy showing an approximately 10 mm irregular elevated obstructive lesion at the bronchial inlet (marked with a black asterisk), consistent with multilevel airway obstruction; (E) Preoperative flexible laryngoscopy revealing recurrent tracheal stenosis, with a large subglottic mass (marked with a white asterisk); (B) Intraoperative bronchoscopy confirming thorough excision of the irregular elevated obstructive lesion at the bronchial inlet, with a patent airway; (F) Intraoperative flexible laryngoscopy demonstrating a patent subglottic region after complete resection of the large subglottic mass, with the placed T‐tube clearly visible in the image; (C) Bronchoscopy at 6 months postoperatively (after T‐tube removal), revealing no residual lesions or recurrence at the prior bronchial inlet involvement site; (G) Flexible laryngoscopy at 6 months postoperatively, showing an unobstructed subglottic region with no evidence of restenosis; (D) Bronchoscopy at 48 months postoperatively, confirming sustained complete airway patency at the previously involved bronchial inlet; (H) Flexible laryngoscopy at 48 months postoperatively, with no restenosis or recurrent lesions at the prior subglottic site.

FIGURE 2.

Laryngo‐thoracic contrast‐enhanced CT findings: Contrast‐enhanced CT image showing an endotracheal tube (mildly right‐deviated) with intraluminal soft tissue density; a 26 × 20 mm subglottic mass obstructing the airway, extending superiorly to induce bilateral vocal cord thickening and glottic stenosis, and inferiorly involving the trachea and main bronchi with wall thickening; a 10 × 11 mm nodule identified at the carina.

FIGURE 3.

Histopathological findings (Hematoxylin–eosin [HE] staining). HE staining demonstrating fibrogranulation tissue proliferation accompanied by mixed acute and chronic inflammatory infiltrates, marked focal histiocytic hyperplasia, and emperipolesis (defined as lymphocyte engulfment by histiocytes).

3. Discussion

RDD, a rare clonal histiocytic neoplasm, manifests as isolated lesions or coexists with autoimmune, genetic, and malignant conditions due to tissue infiltration by activated histiocytes [3]. While the molecular pathogenesis remains incompletely elucidated, emerging evidence implicates the dysregulation of the MAPK/ERK pathway (activating mutations in 50% of cases) and cyclin D1 overexpression (90% of cases) as key contributors [4]. Immune dysregulation further underpins RDD pathogenesis, with clonal histiocytic proliferations harboring somatic mutations in RAS pathway genes (NRAS/KRAS). Although epidemiological links to IgG4‐related disease (IgG4‐RD) and lymphoproliferative malignancies exist, serum IgG4 levels in this case were normal, highlighting the need for integrated molecular profiling to delineate the inflammatory, immune, and neoplastic interplay in RDD. The patient's antecedent airway pathology and chronic T‐tube‐related mucosal injury may have provided an inflammatory milieu conducive to clonal histiocytic expansion in RDD, though an early subdiagnostic disease cannot be excluded. Confirmation is precluded by a lack of archived tissue. Notably, molecular testing for MAPK/ERK pathway mutations and cyclin D1 expression was not performed in this case due to limited residual tissue and the absence of routine molecular profiling for RDD in our practice at that time. This lack of molecular data limits interpretation, as the favorable outcome might reflect a less aggressive molecular phenotype, which remains speculative. These findings should therefore be extrapolated with caution to multifocal airway RDD lacking molecular characterization.

RDD comprises three clinical subtypes: nodal (primarily lymph nodes), extranodal (skin, respiratory tract, skeletal system), and mixed presentations [2]. Extranodal RDD is rare, yet upper airway involvement—typically nasal cavity, larynx, or trachea—often presents as compressive intraluminal or extramural masses. Females of middle age are predominantly affected in laryngotracheal cases, consistent with our patient. Anatomical distribution in ENT regions includes nasal cavity (50%), larynx (25%), paranasal sinuses (18%), and combined tonsillar/tracheal involvement (6.3%) [5]. Dyspnea was the predominant symptom, aligning with our patient's presentation. Hoarseness and airway obstruction may mimic laryngeal carcinoma, while chronic inflammatory involvement is frequently misdiagnosed as asthma.

The differential diagnosis includes amyloidosis, carcinoma, and cysts. Laryngeal amyloidosis presents as hypodense CT lesions with punctate calcifications, whereas subglottic carcinoma may show subtle enhancement [2]. Histopathological confirmation remains definitive, requiring CD68+/S‐100+/CD1a− immunophenotype [5]. Emperipolesis—a hallmark feature of RDD—was observed in our case, alongside concordant immunohistochemical markers (CD1a−, CD68+, S‐100+, Ki‐67 < 5%).

While RDD typically follows an indolent course, localized compressive lesions necessitate surgical intervention, particularly for airway obstruction. Pharmacological options include corticosteroids, immunomodulators (e.g., thalidomide or rituximab), though adverse effects of thalidomide such as teratogenicity, peripheral sensory neuropathy, and amenorrhea restrict its use in specific patient populations, and chemotherapy (e.g., methotrexate or cladribine) [3]. Radiotherapy is reserved for unresectable lesions, and targeted therapies (e.g., cobimetinib) remain investigational. Surgical debulking minimizes recurrence risk in subglottic/tracheal cases, often supplemented by corticosteroids.

Our case demonstrates three pivotal advances: (1) An exceptionally rare, anatomically novel pattern of multifocal concomitant subglottic‐tracheal involvement; (2) Definitive disease control through surgical intervention alone, with no additional therapeutic interventions postoperatively; (3) The longest documented clinical remission (48 months), confirmed by serial endoscopic surveillance. These outcomes support Abla et al.'s consensus [3] for resection in localized RDD and suggest extending its applicability to select complex multifocal subglottic‐tracheal disease that is characterized by resectable lesions and no systemic involvement, in which guidelines typically prioritize systemic therapy.

4. Conclusion

Surgical resection with no additional therapeutic interventions postoperatively achieved sustained disease‐free survival over 48 months in this multifocal subglottic‐tracheal RDD case. This provides clinical evidence supporting the feasibility of localized surgical management for select multifocal subglottic‐tracheal RDD with completely resectable lesions, no systemic involvement, and favorable anatomical accessibility, offering a valuable therapeutic alternative for clinical decision‐making rather than a universal benchmark. Crucially, unlike nodal or single‐site extranodal RDD often managed with observation or surgery [3], our data demonstrate that even complex multifocal tracheal disease can achieve durable remission via resection alone. Multidisciplinary team (MDT) coordination (otolaryngology, respiratory medicine, anesthesiology) facilitated optimized perioperative planning, enhancing precision and outcomes. Rigorous bronchoscopic surveillance confirmed durable remission, underscoring the necessity of longitudinal monitoring.

Notably, this study is limited by its single‐case design. First, surgical resection alone cannot be generalized to all multifocal RDD patients, given RDD's substantial heterogeneity in clinical presentation, anatomical localization, and molecular subtypes. Second, the absence of a control group precludes a comparative analysis of surgical resection and adjuvant therapy in multifocal airway RDD. Our findings should, thus, be interpreted as a proof‐of‐concept for select cases, rather than a standardized treatment recommendation. Prospective multicenter case series or registries with larger cohorts are needed to validate this treatment strategy and identify patient subgroups most likely to benefit from surgical resection alone.

Crucially, integrating molecular profiling with clinical data is vital to advancing precision medicine, addressing the gap in understanding how genetic features influence treatment responses and ultimately improving patient outcomes.

Funding

This study was supported by the Basic Research Project of Wenzhou City (Y20240051). The author(s) declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Ethics Statement

Ethical approval to report this case was obtained from the Ethics Committee of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2025‐K‐159‐01).

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.