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What was causing this previously healthy 12-year-old boy to have nasal obstruction, increasing hoarseness and difficulty speaking, tender and swollen lymph nodes on his neck and recurring deep neck abscesses? That's the question Samantha M. Moore, BS, of the Medical College of Wisconsin in Milwaukee, and colleagues tackled in a case reported in .

CT imaging of the neck with contrast performed during his initial admission suggested suppurative lymphadenitis. Despite surgical drainage of the lymph nodes and treatment with IV ampicillin and sulbactam, the swollen lymph nodes on his neck persisted.

Results of the following tests were all within normal limits:

• Haemophilus, tetanus, and pneumococcal antibody titers
• QuantiFERON-TB Gold test
• Serum immunoglobulin G (IgG), IgM, IgA, and IgE levels
• Absolute lymphocyte count
• Neutrophil phenotype and function
• Angiotensin-converting enzyme level
• HLA-B27 test
• Antinuclear antibody level

Clinicians performed an MRI of the neck with gadolinium contrast, which revealed bulky, enlarged cervical lymph nodes on both sides of the neck. Additionally, clinicians noted enhancing nodules in the left laryngeal ventricle (2.3 × 1.6 × 1.2 cm), right false vocal cord, and right tracheal wall (0.6 × 0.4 cm).

Further investigations, including a nasal endoscopy, awake flexible laryngoscopy, and operative microlaryngoscopy revealed yellow submucosal masses in the left nasal cavity, left laryngeal ventricle, and right trachea, as well as weakness of the left vocal cord.

Clinicians then biopsied the tracheal, laryngeal, and nasal cavity masses, and excised one of the left cervical lymph nodes for biopsy.

Histopathologic analysis identified a prominent infiltrate of benign-appearing histiocytes with numerous forms showing emperipolesis and some nuclei showing distinct central nucleoli. Results of immunohistochemical staining in these cells were positive for S100 and negative for CD1a.

Clinicians considered several differential diagnoses, including Castleman disease, inflammatory pseudotumor, and sarcoidosis, before arriving at a diagnosis of sinus histiocytosis with massive lymphadenopathy, or Rosai-Dorfman disease.

Discussion

Originally described in 1969 by Rosai and Dorfman, Rosai-Dorfman disease, is a benign, proliferative disease of unknown etiology, case authors noted. The relative rarity of Rosai-Dorfman disease and its range of presenting symptoms can make diagnosing it a challenge for physicians, case authors wrote. And the progressive laryngotracheal involvement observed in their patient is extremely rare, they added.

Linked with viral infections, immune-related disorders, and genetic mutations, Rosai-Dorfman disease occurs most often in children and young adults, at an average age of 20, case authors wrote. About four times as many males as females are affected.

The classic, nodal form of the disease typically presents with enlarged but painless lymph nodes on the head and neck. However, in addition to the head and neck, in about 43% of patients, the disease extends beyond the lymph nodes to also affect the skin, soft tissues, and central nervous system.

However, the may not cause any symptoms, depending on the area affected and disease burden, the group wrote. According to a recent study of 31 known cases of pediatric Rosai-Dorfman disease with head and neck involvement, "58% had unifocal disease with a predilection for the nasal cavity and paranasal sinuses," authors noted. And only one other patient has been reported to have the progressive involvement seen in this patient, the group noted.

Results of lab tests and imaging tend to be nonspecific, the group explained, thus biopsy is typically required to confirm the of Rosai-Dorfman disease. "The nodal form," they observed, "shows large clustered histiocytes with round-to-oval nuclei, open chromatin, and variably distinct nucleoli with voluminous pale cytoplasm admixed with an inflammatory infiltrate comprising lymphocytes, plasma cells, and granulocytes."

Intact lymphocytes may be observed within the cytoplasm of the histiocytes – i.e., emperipolesis, authors explained. However, this is not necessary for diagnosis. Features that help differentiate extranodal from nodal forms of Rosai-Dorfman disease include "more prominent fibrosis, fewer histiocytes, and scant emperipolesis," the group wrote.

Histologic findings of Rosai-Dorfman disease tend to be positive for S100, CD68, and CD163, and negative for CD1a, they wrote, the latter findings being necessary to exclude a key differential, Langerhans cell histiocytosis (LCH).

According to authors of that cited by the group, "Perhaps the most important differential diagnosis of RDD [Rosai-Dorfman disease] is that of LCH. A diagnosis of RDD by definition requires the exclusion of LCH by negative CD1a or CD207 staining of the histiocytic infiltrate ... Of note, S100 positivity is observed in both RDD and LCH."

As well, Rosai-Dorfman disease shares features with lymphoma and several inflammatory disorders, case authors noted. While Castleman disease clinically resembles Rosai-Dorfman disease, it differs considerably in terms of histologic findings, authors wrote, depending on "whether it is the hyaline vascular or plasma cell variant."

"Inflammatory pseudotumor manifests as nodal or tissue masses composed of reactive lymphoplasmacytic infiltrates, histiocytes, spindled fibroblasts, or myofibroblasts; however, histiocytes are negative for S100," the group wrote.

Patients with sarcoidosis will have enlarged lymph nodes on the head and neck as well as mucosal nodules in the nose and larynx, they noted, but will have microscopic evidence of granulomas and often multinucleated giant cells. Once Rosai-Dorfman disease has been diagnosed based on microscopic findings, authors noted that "fluorodeoxyglucose positron emission tomography/CT may be useful for staging evaluation given its sensitivity and specificity for both nodal and extranodal regions."

When diagnosing young patients, an MRI of the whole body is typically preferred over CT scans to minimize their exposure to radiation. Rosai-Dorfman disease is typically self-limiting without treatment, although prognosis may vary, the group wrote. Cases such as the one reported here "showing persistent disease associated with mass effects [may warrant] management with corticosteroids, surgical resection, sirolimus, radiation, chemotherapy, or immunomodulatory therapy." In the absence of official treatment guidelines for Rosai-Dorfman disease, authors suggested that monitoring regularly for recurrence is critical.

"Albeit rare, RDD should be considered in the differential diagnosis for both children and adults with cervical lymphadenopathy and airway lesions," case authors concluded, noting that it is important to assess and manage the risk of airway obstruction. Awareness of the clinical features of Rosai-Dorfman disease, along with histopathologic assessment can help clinicians make "a timely diagnosis and ensure appropriate treatment."

In this case, while the initial treatment with systemic steroids improved symptoms significantly, therapy was discontinued when the patient experienced substantial weight gain as a result, and the lesions affecting his larynx and trachea recurred. Subsequently, systemic sirolimus therapy was effective, authors noted, along with one surgical debulking of his airway disease.

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