Rosai-Dorfman Disease: Report of a Case Presenting as a Midline Thyroid Mass

Rosai-Dorfman disease (RDD), a rare histiocytic proliferative disorder of unknown cause, was first established as a distinct clinicopathologic entity in 1969.1 It has a worldwide distribution and affects all age groups, with a mean age of onset of 20.6 years. Although the classic presentation of RDD is that of massive, bilateral, painless cervical lymphadenopathy, extranodal disease is common, often with particular predilection for the head and neck region (75% of cases). Involvement of the thyroid gland, however, is extremely rare and has been reported in only 3 cases.2 We describe an unusual case of RDD, which both clinically and radiologically presented as a thyroid nodule but which was histologically and immunohistochemically confirmed to be RDD involving only 2 small anterior cervical lymph nodes, one of which was a thyroid isthmic lymph node.

A 38-year-old white woman presented in early January 2001 with a 6-month history of a painless, enlarged anterior neck mass. There were no other associated clinical symptoms. Her medical history was unremarkable, and she had been in general good health. On physical examination, a firm, smooth, freely mobile, nontender nodule was palpable at the level of the thyroid isthmus. No other masses or lymph nodes were noted. The results of the remainder of her otolaryngologic and systemic examination were within normal limits. An ultrasound of the thyroid gland revealed the presence of a septated and avascular, 1.5-cm cystic mass within the thyroid isthmus (Figure 1). Two fine-needle aspiration (FNA) biopsy specimens of the neck mass were performed at an outside institution during a 4-month period. Both FNA biopsy specimens showed findings consistent with a lymph node. The anterior neck mass progressively increased in size. A magnetic resonance imaging scan performed 6 months after the last FNA biopsy revealed the presence of both a 1-cm nodule related to the thyroid isthmus and a separate 2-cm nodular area below it (Figure 2). An isthmectomy with removal of the isthmic mass and a resection of the second pretracheal mass was performed. Gross inspection of the resected neck specimens revealed a 2.0-cm and a 1.2-cm brown-gray and tan nodular mass. Histologically, both specimens showed similar features, namely, the presence of a lymph node with distortion of its architecture.

Normal thyroid tissue was present at the periphery of the isthmic nodule separated from it by the nodal capsule (Figure 3). At low power, normal-appearing lymphoid tissue was found to alternate with pale-appearing areas composed of sheets of histiocytes admixed with lymphocytes and plasma cells. Follicular centers were widely separated by broad sheets of histiocytic cells with abundant foamy cytoplasm, showing prominent phagocytosis of intact lymphocytes and plasma cells, a phenomenon referred to as emperipolesis (Figure 4). The histiocyte nuclei were round to oval and vesicular to hyperchromatic, with abundant amphophilic to eosinophilic, granular to foamy or clear cytoplasm. Numerous plasma cells were also associated with these histiocytes. The surrounding thyroid tissue in the isthmic nodule was uninvolved by this process. Immunohistochemical staining for S100 protein was positive and revealed granular, cytoplasmic staining of the large histiocytes (Figure 6). A final diagnosis of RDD was made. A review of the cytologic slides from the previous 2 FNA biopsy specimens performed at an outside laboratory revealed the presence of numerous lymphocytes admixed with large histiocytic cells, demonstrating the phenomenon of emperipolesis. These cells had either single or multiple large nuclei, some with a prominent nucleolus and abundant foamy cytoplasm containing intact lymphocytes and plasma cells (Figure 5). The postoperative recovery was uneventful. Currently, at 3 months after surgery, the patient is healthy without any recurrent lymphadenopathy or recurrence of this disease at other sites.

The present case demonstrates an unusual clinical presentation of RDD as a thyroid isthmic nodule, which histologically revealed RDD involving 2 anterior cervical lymph nodes, of which one was closely associated with the thyroid isthmus. The latter presented clinically as an avascular, cystic thyroid mass on sonography. To our knowledge, there has been no report of anterior midline cervical lymphadenopathy as the sole manifestation of RDD in the literature. Involvement of the thyroid gland by RDD is also extremely rare, and thus far, only 3 other cases have been reported in literature. All of these cases were also observed in white women. Two also had associated massive lymphadenopathy. In the first reported case, the thyroid involvement probably resulted from secondary extension of the RDD from the many affected adjacent lymph nodes.3 The second case presented as an 8-month course of subacute thyroiditis.4 The third presented as an incidental finding of a mobile thyroid nodule during a routine physical examination. The patient was clinically and serologically confirmed to have underlying autoimmune thyroiditis. A FNA biopsy of the nodule was compatible with autoimmune thyroiditis. The patient had a mild hypercalcemia. Despite T4 suppression treatment, the nodule increased in size and mild lymphadenopathy developed. Histologically, both the thyroid nodule and the adjacent lymph nodes showed the presence of RDD. There was no other systemic manifestation of RDD. Postoperatively, the patient remained disease free.

The present case is unusual in that, although it clinically presented as an extranodal form of RDD involving the thyroid isthmus, histopathologically the isthmic nodule was found to be an affected peri-isthmic lymph node, whereas the adjacent thyroidal tissue was uninvolved by the pathological process. The only other involved site was an additional pretracheal lymph node. Most cases of RDD present with lateral cervical lymphadenopathy, whereas the present case is one of an anterior neck node presentation. The small size of the affected tissue, the extremely unusual location, and the absence of involvement of any other lymph nodes or organs are unusual for this disease. Extranodal sites are affected either alone or simultaneously with lymph node disease or may result from extension from adjacent nodes.5 Head and neck involvement by RDD is present in 75% of cases with extranodal disease. In this region, the sites most frequently involved include skin, nasal cavity, paranasal sinuses, nasopharynx, parotid gland, submandibular gland, larynx, temporal bone, infratemporal fossa, pterygoid fossa, meninges, and the orbit.6 Osseous involvement is rare and may involve one or multiple bones. The lesions in bone need to be differentiated from Langerhans cell histiocytosis and other histiocytic disorders that affect bone. Although ocular involvement is rare and mostly localized to the eyelids, corneal infiltrates and uveitis have also been reported as a rare manifestation of RDD.7 Other sites of involvement include the breast, kidneys, intestinal tract, liver, and pancreas. Primary intraparenchymal involvement of the central nervous system has also been reported. Clinically, the patients may experience febrile episodes with elevated erythrocyte sedimentation rate and neutrophilia, anemia, and a polyclonal hypergammaglobulinemia. Also, RDD may be associated with immune-mediated disorders, including polyarthralgia, glomerulonephritis, asthma, and type 1 diabetes mellitus.8 The origin of the disease is unknown; an unidentified infectious cause or altered immune responses are speculative etiologic agents. Inconsistent results have been found following the use of various treatment modalities, including antibiotics, surgery, radiotherapy, and chemotherapy. Typically, RDD undergoes spontaneous remission after a protracted course but may develop recurrences. Rarely, the involvement of vital organs may lead to death.

Only a few cases of RDD diagnosed by FNA biopsy have been reported in the literature.9 The differential diagnosis of RDD on FNA biopsy may include reactive and neoplastic lesions. In the appropriate clinical setting, however, the phenomenon of emperipolesis may be of great utility in the FNA biopsy diagnosis of RDD. In retrospect, the extremely atypical presentation of RDD in our case precluded the initial FNA biopsy diagnosis.

Immunohistochemical stains are helpful in differentiating RDD from other histiocytic proliferations. The RDD histiocytes are strongly and consistently positive for S100 protein. They also express positivity for the macrophage lineage markers, such as HAM-56, CD14, CD68, and MAC-387. A smaller percentage of RDD cells are immunoreactive against CD30 and α₁-antitrypsin. The plasma cells present demonstrate a polyclonal pattern of proliferation with cytoplasmic positivity for both κ and λ light chains. Disorders that warrant a differential diagnosis from RDD include reactive sinus hyperplasia, Langerhans cell histiocytosis, Hodgkin disease, metastatic carcinoma, malignant melanoma, and lymphoma.10 Langerhans cell histiocytosis, like RDD, demonstrates a positive expression with S100 staining. However, cells of Langerhans cell histiocytosis lack lymphophagocytosis and ultrastructurally reveal the presence of the characteristic rod-shaped Birbeck granules. CD1a is expressed in Langerhans cell histiocytosis but not in RDD. Lacunar cells of nodular sclerosis Hodgkin disease may on occasion be confused with RDD cells. However, the Reed-Sternberg cells and their variants do not exhibit emperipolesis. They are S100 protein negative, CD15 positive, and CD30 positive. Negative staining for HMB-45 and pankeratin differentiate RDD from melanoma and metastatic carcinoma.

In summary, our case report demonstrates well the difficulties that may arise in diagnosing this rare entity in an atypical clinical setting. The diagnosis of RDD must be considered in the differential diagnosis when atypical histiocytes are present on the FNA biopsy specimen. Surgical biopsy and specific immunohistochemical stains help to confirm the diagnosis.