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Rosai-Dorfman disease of the parotid gland: cytologic and histopathologic findings with immunohistochemical correlation.

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown origin and a distinct clinicopathologic entity also known as sinus histiocytosis with massive lymphadenopathy, which can present as an enlargement of the major salivary glands. Most cases manifest primarily with painless cervical lymphadenopathy, although associated extranodal involvement is not infrequent. (1,2) Extranodal disease may be the initial and sole manifestation of the disorder; however, extranodal manifestation of the disease in the major salivary gland is rare. (2,3) Involvement of the extranodal head and neck sites appears to be more common in patients with immunologic abnormalities. (3) We describe the cytologic and histopathologic features of a case of Rosai-Dorfman disease that involved the right parotid gland in a 48-year-old man with systemic lupus erythematosus (SLE). We also characterize abnormal histiocytic cells of the infiltrate immunohistochemically and discuss the differential diagnosis, possible etiologic agents, and pathogenetic mechanisms.


Clinical Findings

A 48-year-old man with a long history of SLE, arthropathy, and cardiac dysrhythmia was seen by an ear, nose, and throat surgeon because of persistent enlargement of the right parotid gland. Surgical history included excisional biopsy of the left parotid gland 18 years ago. Histologic examination at that time revealed mild interstitial lymphocytic infiltration and mild fibrosis without effacement of glandular tissue, consistent with mild nonspecific sialoadenitis. Several lymph nodes removed at the same time demonstrated no characteristic infiltration of the sinuses by abnormal histiocytic cells. Current laboratory studies demonstrated mild normocytic anemia without other abnormalities. Because of worsening discomfort and gland enlargement, the patient underwent surgical excisional biopsy of the right parotid gland.

Cytologic Findings

Smears made by touch imprint technique were cellular and demonstrated numerous histiocytic cells, plasma cells, and lymphocytes. Occasional neutrophils were present as well. Histiocytic cells were large with round-to-oval pale staining nuclei, prominent small nucleoli, and abundant, occasionally vacuolated cytoplasm. The cytoplasm of many histiocytic cells contained intact lymphocytes and plasma cells (Figure 1). Some of the lymphocytes in the cytoplasm of the histiocytes were surrounded by pale halos. Large binucleated and multinucleated forms were also present.


Histopathologic Findings

Grossly, the excised salivary gland tissue was received in multiple pieces, with the largest fragment measuring 6 cm in greatest dimension, and appeared yellowish tan and slightly lobulated. The cut surface was firm with thin, ill-defined fibrotic bands. Discrete masses were not seen. Microscopic examination revealed extensive replacement of the salivary gland parenchyma by an infiltrate consisting of many histiocytic cells admixed with lymphocytes and numerous mature-appearing plasma cells. Histiocytic cells of the infiltrate were large and contained vesicular nuclei with delicate nuclear membranes, distinct nucleoli, and abundant pale-to-eosinophilic cytoplasm. Intact erythrocytes, lymphocytes, and plasma cells were engulfed in the cytoplasm of the many histiocytic cells, a process known as emperipolesis (Figure 2). Bands of fibrous tissue that dissected the involved gland and occasional multinucleated histiocytic cells were seen. Small residual ducts and islands of intact salivary gland acini predominantly composed of serous-type glandular epithelium were present (Figure 3).


Immunohistochemical Findings

Immunohistochemical studies were performed on deparaffinized tissue sections using the labeled streptavidin-biotin method and an autostainer (Dako Corporation, Carpinteria, Calif). The histiocytic cells were strongly reactive with antibodies against S100 protein (1:800 dilution, Dako) (Figure 4) and with HAM-56 (prediluted, Enzo Diagnostics, Farmingdale, NY). However, the same cells were nonreactive with antibodies directed against CD1a (prediluted, Immunotech, Marseille, France). Plasma cells in the infiltrate demonstrated a polyclonal pattern of light chain staining. Leukocyte common antigen (prediluted, Dako) stain demonstrated membranous staining pattern of the histiocytic cells and engulfed lymphocytes. All immunohistochemical studies had satisfactory positive and negative controls.



Practically, the most common problem in differential diagnosis in cases of lymph node involvement is to distinguish sinus histiocytosis with massive lymphadenopathy from so-called sinus hyperplasia (sinus histiocytosis), a nonspecific reaction to a wide variety of agents, although, theoretically, many diseases can resemble Rosai-Dorfman disease morphologically. Both Rosai-Dorfman histiocytes and normal sinus histiocytes in the lymph node are strongly reactive with HAM-56 (panmacrophage antibody); however, a clear difference exists in the expression of the S100 protein (strongly expressed by Rosai-Dorfman histiocytes and negative in normal sinus histiocytes). (4) In our case, in the absence of extensive lymph node involvement, the differential diagnosis was more limited and included several different malignant and benign processes in which phagocytosis of cells can be a prominent finding. Malignant conditions that one should consider include carcinoma and melanoma metastatic to the salivary gland, since malignant cells may show a propensity to phagocytose hematopoietic cells. Involvement by Langerhans cell histiocytosis should also be considered, although Langerhans cells have distinctive morphologic features different from the histiocytes of Rosai-Dorfman disease. Nuclei of Langerhans cells are smaller and often irregular, with folding, grooves, and fine chromatin without prominent nucleoli. Emperipolesis or lymphocytophagocytosis, which was easily detectable in our case, is not a feature of Langerhans cells. In Langerhans cell histiocytosis, a prominent eosinophilic component, including formation of eosinophilic abscesses, is frequently seen, which was not present in our case. Both Rosai-Dorfman histiocytes and Langerhans cells strongly express S100 protein; however, Langerhans cells are more likely to be CD1a positive. (4) In our case, we observed membranous positivity for leukocyte common antigen in the histiocytes that infiltrated the salivary gland, which in our opinion can be regarded as additional evidence that these cells originate from bone marrow-derived monocytes or macrophages. This immunohistochemical finding has been reported in at least one other study. (5)

First described in 1969 in 4 patients, (1) the Rosai-Dorfman disease is now considered a well-defined clinicopathologic entity, and a case registry has been established at the Yale School of Medicine to study the disorder. Most patients are young (mean age of onset, 20.6 years), although there may be wide age distribution at presentation. (1,2) There is no apparent race predominance, with disease occurring slightly more often in male patients. (2) Most patients present with bilateral, painless cervical lymphadenopathy, but other lymph node groups, including mediastinal and inguinal, can be involved as well. (1,2) Extranodal involvement of at least one site is not uncommon and can rarely be an initial and the only manifestation of the disease. The most common extranodal manifestation of disease was in the head and neck area and occurred in approximately 22% of the patients. (2,6) The most common site of the ear, nose, and throat involvement was the nasal cavity, with the major salivary gland being the second most common site. (2,3,6) In the cases from the disease registry, 22 patients with nodal disease had involvement of the major salivary gland (2); however, all cases had associated lymph node involvement, and it was not clear whether these cases represented intrasalivary lymph node or extranodal disease. (2) In our case, there was definite involvement of the salivary gland itself; however, a small extrasalivary lymph node removed at the time of surgery demonstrated partial effacement of the architecture by an infiltrate similar to that seen in the salivary gland. Whether this represented extension of the process from the lymph node to the parotid gland or vice versa was not clear.

The characteristic pathologic feature of this disease is proliferation of distinctive histiocytic cells that demonstrate emperipolesis in the background of a mixed inflammatory infiltrate, consisting of moderately abundant plasma cells and lymphocytes. (2,3,6) This commonly results in the effacement of the involved organ architecture with eventual formation of fibrous bands.

Although emperipolesis is not unique to this condition, in the appropriate clinical and pathologic setting, the presence of this phenomenon in the histiocytes that express S100 protein is considered diagnostic of Rosai-Dorfman disease. (3) This characteristic feature of the histiocytes is helpful in cytologic evaluation of the specimens obtained from the salivary gland and lymph nodes, (5) where this entity is in the differential diagnosis. The phenomenon of emperipolesis may represent abnormal or incomplete phagocytosis of lymphocytes by antigen-presenting cells and could be related to the abnormalities of the immune response to environmental or infectious agents. The presence of the human herpesvirus 6 and to a lesser extent the Epstein-Barr virus genome was demonstrated by the in situ hybridization technique in the abnormal tissue histiocytes from the patients with Rosai-Dorfman disease. (7) Another study, however, failed to demonstrate Epstein-Barr virus carriage by histiocytic cells. (8) On the other hand, expression of the late human herpesvirus 6 viral antigen gp106 was detected in the cytoplasm of abnormal histiocytes by immunohistochemistry in the involved lymph node tissue. (9) Whether this represents a true pathogenetic involvement of this ubiquitous herpesvirus remains to be elucidated.

Rosai-Dorfman disease generally has a long-term clinical course characterized by exacerbations and remissions and appears to undergo complete remission in most patients. (2,10) However, a subset of patients who had immunologic abnormalities at or before presentation was characterized as having less favorable prognosis and a higher mortality rate. (10)

In our case, Rosai-Dorfman disease occurred in a patient with an established immunologic disease (SLE) who was undergoing treatment with low-dose prednisone and hydrochloroquine sulfate. After follow-up of 2 years, no significant lymphadenopathy developed, although the patient continued to have exacerbations and remissions of the swelling of his submandibular and parotid salivary glands and in addition developed lacrimal gland enlargement.

From a clinical perspective, the diagnosis of Rosai-Dorfman disease should be considered in patients with immunologic disorders (such as SLE) who develop salivary and/or lacrimal gland enlargement. Fine-needle aspiration and/or surgical biopsy is helpful in confirming the diagnosis and excluding a neoplastic process, which may require more radical treatment.


(1.) Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: newly recognized benign clinicopathologic entity. Arch Pathol Lab Med. 1969; 87:63-70.

(2.) Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease): review of the entity. Semin Diagn Pathol. 1990; 7:19-73.

(3.) Goodnight JW, Wang MB, Sercarz JA, et al. Extranodal Rosai-Dorfman disease of the head and neck. Laryngoscope. 1996;106:253-256.

(4.) Eisen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus histiocytes with massive lymphadenopathy (Rosai-Dorfman disease). Semin Diagn Pathol. 1990;7:74-82.

(5.) Pettinato G, Manivel JC, d'Amore ESG, et al. Fine needle aspiration cytology and immunohistochemical characterization of the histiocytes in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Syndrome). Acta Cytol. 1990;34: 771-777.

(6.) Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: ear, nose and throat manifestation. Arch Otolaryngol. 1978;104:687-693.

(7.) Levine PH, Jahan N, Murari P, et al. Detection of human herpesvirus 6 in tissues involved by sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). J Infect Dis. 1992;166:291-295.

(8.) Tsang WYW, Yip TTC, Chan JKC. The Rosai-Dorfman disease histiocytes are not infected by Epstein-Barr virus. Histopathology. 1994;25:88-90.

(9.) Luppi M, Barozzi P, Garber R, et al. Expression of human herpesvirus-6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol. 1998;153:815-823.

(10.) Foucar E, Rosai J, Dorfman RF. Immunologic abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol. 1984;82:515-525.

Accepted for publication April 17, 2001.

From the Department of Pathology, Brody School of Medicine at East Carolina University, Greenville, NC.

Reprints: Ridas Juskevicius, MD, Department of Pathology, Brody School of Medicine at East Carolina University, 600 Moye Blvd, Brody Medical Sciences Bldg, Room 7S-10, Greenville, NC 27858-4354 (e-mail:
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Author:Juskevicius, Ridas; Finley, James L.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Oct 1, 2001
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