Rosai–Dorfman disease of the tonsil in a 4-year-old boy: Case report and review of the literature

1. Introduction 

Rosai–Dorfman disease (RDD) is a disease of unknown etiology that has a wide age distribution, but mainly involves children and adolescents [1]. It commonly presents as cervical lymphadenopathy, which upon microscopic examination exhibits the characteristic finding of sinus infiltration by histiocytic cells showing pale granular cytoplasm, round nuclei and distinct red central nucleoli. These histiocytic cells generally exhibit emperipolesis, or lymphophagocytosis, and are positive for S-100, and negative for CD1a [1], [2]. Extranodal manifestations of SMHL are less common than that of lymph nodes, and a tonsillar presentation even more rare [1]. This is the sixth case of tonsillar involvement, and the first to show only reactive hyperplasia in the associated enlarged lymph nodes [1], [3], [4], [5].

2. Case report 

The patient, a 4-year-old African American male, presented to the urgent care clinic with cervical lymphadenopathy which began 4 months earlier. He was complaining of noisy breathing at night for several months duration, and an increasing hoarseness of voice for a few weeks duration. There was no significant past medical history. Family history was significant for sickle cell anemia in the maternal lineage. He was tested for various possible infectious etiologies and was found to have IgG antibodies for Epstein–Barr virus (EBV) and for cytomegalovirus (CMV). Cat scratch IgG and IgM antibodies were negative. Examination revealed cervical lymphadenopathy involving both anterior cervical chains. The lymph nodes were moderately enlarged, especially on the right, and were mildly tender and mobile. The tonsils were noted to have 2+ 3+ enlargement. Physical examination was otherwise normal. A computed tomography (CT) of the neck with contrast was performed, which confirmed the cervical lymphadenopathy. The largest lymph node was in the right jugulodigastric chain measuring 2.6cm in its transverse dimension. On the left, the largest node in the posterior cervical chain measured 2.4cm in length. There were also bilaterally enlarged retropharyngeal lymph nodes. The adenoids and tonsils were also enlarged. The bones, soft tissues, paranasal sinuses and mastoid cells were normal. A chest X-ray was negative for adenopathy. The patient was scheduled for an excisional lymph node biopsy, with intraoperative consultation. A 1.2cm lymph node was removed, and wedge biopsies were taken from adjacent enlarged masses/lymph nodes. Microscopically the lymph node showed follicular lymphoid hyperplasia with reactive changes. There was capsular fibrosis, focal sclerosis, and preserved architectural features. There was no evidence of neoplasia or specific morphologic changes. It was decided that the hoarseness of voice and disturbed breathing symptoms were likely secondary to tonsillar and adenoid hypertrophy. The patient was scheduled for a tonsillectomy.

One year following the tonsillectomy, the cervical lymph nodes had decreased in size, and the patient was well and healthy. He continues to do well without further complaints or adenopathies.

2.1. Pathologic findings 

On gross examination, the tonsils appeared enlarged, at 3.6cm in maximal dimension. Microscopic examination showed follicular lymphoid hyperplasia. In the interfollicular zones and partially involving the follicles, there were rare lesions consisting of sheets of large histiocytic cells with abundant cytoplasm, large round nuclei and prominent nucleoli. The cytoplasm of these cells showed intact phagocytized cells including lymphocytes and plasma cells. Immunoperoxidase staining was performed and showed histiocytic cells positivity for S-100 and CD163, with negative CD30 (Leica Biosystems Newcastle, Ltd, Newcastle upon Tyne, UK) (Fig. 1). The diagnosis of Rosai–Dorfman disease (or SHML) was made. A retrospective review of the previously excised lymph node revealed no diagnostic evidence of SHML.

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Fig. 1. (A) Gross appearance of a tonsil showing focal involvement by (SHML) as tan-white discrete foci of discolorations (circle). (B) Dilatation of interfollicular sinuses and germinal center, focally, by histiocytic infiltrate (hematoxylin and eosin, original magnification 10×). (C) Histiocytes have prominent nucleoli, and display emperipolesis, note the intact lymphocytes within the cytoplasm (hematoxylin and eosin, original magnification 40×). (D) Histiocytes are diffusely S-100 positive (S-100 immunostain, original magnification 40×).

3. Discussion 

Rosai–Dorfman disease (RDD) is a rare, non-neoplastic histiocytic disorder. It is considered among the histiocytoses of childhood, which includes Langerhans cell histiocytosis, hemophagocytic syndrome, juvenile xanthogranuloma and malignant histiocytosis [6]. SHML was first described by Destombes in 1965 who described it as an “adenitis with lipid excess”, or histiocytose lipidique ganglionnaire pseudotumorale de Destombes [7]. In 1969 and 1972 it was further defined and recognized as a distinct clinico-pathologic entity, by Rosai and Dorfman, who also established an international registry of this disease. The results of this registry were published in 1990 [1], [8], [9].

SHML is a disease that affects a wide range of ages from birth to 79 years [1], [4], but mainly children and adolescents, with slight male predominance. Non-specific clinical features such as fever, leukocytosis, and hyperglobulinemia can be seen. An increase of ESR is seen in 88% of cases. There have been documented autoimmune associations, including immunological disorders such as Wiskott–Aldrich syndrome, rheumatoid arthritis, or glomerulonephritis, as well as neoplasms including NHL, myeloma, and melanoma [1], [2]. SHML is still a disorder of unknown etiology. Its polyclonal nature and clinical course suggest a reactive process rather than a neoplastic one [10]. The cell of origin is also uncertain, with evidence of macrophage/monocytic origin, and a possible cytokine dysregulation of these cells [11]. Dendritic cell origin has also been proposed [12]. A viral etiology has been suspected in some cases, including HHV6 and to a lesser extent EBV, through in situ hybridization techniques [13], or high viral titers [1], [5]. Evidence of Parvovirus B19 was also seen in four cases, by immunohistochemical staining [14].

From a pathologic standpoint, excised lymph nodes involved by SHML are often matted, yellow–white, and show fibrosis of the capsule and pericapsular adipose tissue. Microscopic examination commonly reveals marked dilation of the sinuses expanded by sheets of cells, predominantly consisting of large histiocytes with abundant eosinophilic or occasionally foamy cytoplasm, enlarged vesicular round or oval nuclei, well defined nuclear membranes, and a single prominent nucleolus. The follicles and germinal centers can also be partially involved. The histiocytes characteristically exhibit emperipolesis, or lymphophagocytosis, which is a phenomenon in which lymphocytes and occasionally other cells such as neutrophils, plasma cells or red blood cells, are ingested into the cytoplasm of histiocytes, with no degradation. Eosinophils are not generally seen. Mitoses and nuclear atypia are rare. Necrosis is absent. Extranodal SHML shares a similar morphology to the nodal counterparts, appearing as lymphohistiocytic infiltrates in a non-lymphoid organ. They generally exhibit more fibrosis, fewer histiocytes and less emperipolesis. The fibrous stroma often shows prominent vessels with perivascular plasmacytic infiltrate [1], [2]. By immunohistochemistry, the histiocytic cells in SHML usually (but not always) are reactive for S-100, pan macrophage markers such as CD68 and HAM56, pan monocyte markers such as CD11c, CD103, and show variable reactivity for lysozyme, alpha-1 antitrypsin, and alpha one antichymotrypsin. CD1a, if present, is rare [2].

The main differential for SHML is that of a reactive process such as sinus histiocytosis. The two entities can be differentiated by the typical appearance of histiocytic cell nuclei in SHML and the presence of emperipolesis and lymphophagocytosis. Hemophagocytosis can be seen in hemophagocytic lymphohistiocytosis (HLH), but the latter lacks the typical S100 positive cells of SHML. Langerhans cell histiocytosis may also be in the differential, but can be distinguished by its characteristic folded or grooved nuclei, eosinophilic infiltration, and CD1a reactivity. Other differentials are the extremely rare histiocytic sarcoma, and infections caused by histoplasma capsulatum or rhinoscleroma [2]. Storage diseases (Gaucher's, Niemann-Pick) are usually easy to separate based on their morphologic features and special stains (such as PAS).

The most common clinical presentation of SHML is a painless bilateral cervical lymphadenopathy, which in a registry of 423 patients, occurred in at least 87% of them. 43% of cases had at least one site of extranodal involvement in addition to the lymph node involvement, and 23% of cases had extranodal involvement only. Extranodal involvement most commonly includes skin and soft tissue, head and neck regions such as nasal cavity and paranasal sinuses; eye and orbit and salivary glands, and bone. Less frequent areas include the central nervous system, the genitourinary tract, liver, breast, GI, and even heart. Multifocal presentations are common [1], [2]. Tonsillar involvement is rare. A literature review of the English language revealed five other cases of tonsillar involvement by SHML [1], [3], [4], [5]. They included four males and one female. In all cases cervical lymphadenopathy was an associated feature, either due to involvement by SHML, or as seen in this case, a reactive process.

The earliest case described is in 1977 [3]. A 29-year-old male presented with cervical lymphadenopathy of 9 months duration. He also had an increased ESR and hypergammaglobulinemia. Examination revealed tonsillar enlargement, and submandibular gland enlargement. A biopsy of the submandibular gland was diagnosed as “probably inflammatory histiocytic reaction of unknown etiology.” A tonsillectomy was performed, a long with biopsy of another cervical lymph node. The specimens revealed fibrosis and dilatation of the sinuses, with infiltration by the characteristic histiocytic cell with prominent nucleoli exhibiting emperipolesis. Special stains to rule out infectious causes such as GMS and Acid-Fast, were negative. At the time, the patient was presumed to have Hodgkin's disease, and progressive enlargement of the cervical lymph nodes was treated by radiotherapy, followed by chemotherapy. The cervical lymph nodes decreased in size, however the patient was later lost to follow up. The other three patients described in the report had cervical enlargement without tonsillar involvement [3].

In 1987 a 79-year-old man was described who presented with a 35-year history of cervical lymph node enlargement, and 10-year history of nasal obstruction [4]. An indirect laryngoscopy revealed a polypoid protrusion of the larynx, and uneven protrusions extruding from enlarged tonsils. Biopsies of the lymph node, laryngeal polyp, and tonsils revealed a histiocytic and lymphocytic infiltrate that was interpreted as rhinoscleroma. The patient was treated with antibiotics, and the lymphadenopathy improved. Reevaluation of the slides (3 years later) revealed histiocytes with characteristic emperipolesis and S-100 positivity. A retrospective diagnosis of SHML was rendered [4]. A more recent case was published in 1994, and described a 6-year-old girl with a subtle cervical bilateral lymphadenopathy and unilateral tonsillar enlargement [5]. A left submandibular lymph node was also enlarged. Her laboratory data showed an elevated ESR of 33mm, as well as positive IgG EBV titers, with weak IgM. Biopsy of both the lymph nodes and tonsils revealed SHML. S-100 stain was confirmatory. No further treatment was administered, and she was carefully followed as an outpatient [5].

Two other cases of tonsillar involvement are listed in the international registry for SHML [1]. One case presented with repeated bouts of tonsillitis, fever and chills, and whose tonsils were removed 5 months later; and the other case had tonsillar enlargement, greater on the right side, which was treated by tonsillectomy. Both were male, and both had associated cervical lymphadenopathy. Both showed persistence of the disease, at time of publication [1].

4. Conclusions 

SHML is a disease with many clinical presentations, and can involve numerous organs, the most common being lymph nodes. Tonsillar involvement though rare, can occur. Upon review of the literature, tonsillar SHML appears to affect a variety of age ranges, from 4 years old through 79 years old, and has a male predominance. It is always associated with cervical adenopathy, which can be the presenting feature. This is the first reported case in which the cervical lymph nodes were reactive in nature rather than involved by SHML. As in other organs, tonsillar SHML has a generally good prognosis with spontaneous regression, but can require surgical excision to relieve compression symptoms. These incidental findings reaffirm the importance of careful routine histopathologic examination of tonsillectomy specimens, especially in cases where there is an associated cervical lymphadenopathy.