Sinus histiocytosis with massive lymphadenopathy (SHML), also known as RDD, is a rare nonmalignant proliferative disorder first described by Rosai and Dorfman in 1969. Classically, it presents as prominent bilateral, massive, painless cervical lymphadenopathy; low-grade fever, weight loss, leukocytosis, elevated erythrocyte sedimentation rate and hypergammaglobulinemia are often found. Extranodal involvement of at least one site is identified in 43% of RDD cases and only 23% exclusively have extranodal disease.[1
] Documented sites of extranodal involvement include skin, respiratory tract, bone, genitourinary system, oral cavity, central nervous system, eyes/orbit/ocular adnexa, salivary gland, tonsil, breast, soft tissue and heart. The bone marrow is rarely involved.[2
] Most patients with RDD have a complete and spontaneous remission. Some may experience recurrent or persistent but stable lymphadenopathy. In rare cases, the disease follows an aggressive course and may be fatal[3
] and involvement of kidney, lower respiratory tract, or liver has been found to be a poor prognostic sign.[1
] Occasionally, RDD may be associated with autoimmune disorders and hematopoietic malignancies.[4
] The etiology of RDD is unknown though it has been speculated that an occult chronic infection or an aberrant exaggerated immune response to an infectious agent or an antigen causes the initial histiocytic proliferation.[3
RDD is notable for its varied clinical presentations which evoke a wide differential diagnosis. Although correlation of clinical presentation with radiologic and laboratory values is very helpful, the pathologic assessment is pivotal in making the diagnosis. The classic histology is characterized by effacement of nodal architecture and dilatation of lymph node sinuses by lymphocytes, plasma cells and numerous characteristic histiocytes with large vesicular nuclei and abundant clear cytoplasm. Many of these histiocytes, also known as RDD cells, contain intact lymphocytes, and sometimes plasma cells and red blood cells, within their cytoplasm. This process whereby cells enter and transit through a cell evading cellular degradation is known as emperipolesis and was first described by Humble et al
] When extranodal sites are involved, similar morphologic features to the nodal counterpart are seen although with more fibrosis, fewer typical RDD histiocytes, and less prominent emperipolesis.[3
] Immunohistochemical stains are useful when diagnosing RDD as the RDD cells have been found to express pan-macrophage antigens (CD68, HAM56, CD14, etc.), antigens associated with phagocytosis (CD64, Fc receptor for immunoglobulin G), lysosomal activity (lysozyme alpha 1-antitrypsin, alpha1-antichymotrypsin), and immune activation and adhesion molecules (transferring receptor, interleukin 2 receptor).[3
] The most consistent and reliable phenotype for RDD is S100(+), CD68(+) and CD1a(−).
RDD can be encountered in both nodal and extranodal locations, and FNA, a simple, accurate and economic tool, has been widely used for the diagnosis of superficial and deep-seated lesions. Familiarity with the cytomorphologic features of RDD is important as prognosis and treatment are quite different from other benign or malignant diseases for which it may clinically masquerade. Review of the literature has revealed 49 reported cases of RDD diagnosed by FNA . Typically, FNA specimens show non-cohesive, diffusely distributed, enlarged histiocytes. These cells have variable nuclei, abundant cyanophilic cytoplasm and demonstrate emperipolesis of lymphocytes, plasma cells and occasionally erythrocytes.[19
] Although the nuclear shapes vary from round to extremely bizarre configurations, the chromatin is fine and evenly distributed and the nucleoli are usually not prominent. Occasionally, atypical morphology may be seen and, when present, it can lead to a misdiagnosis of malignancy.[19
] Lymphocytes, plasma cells, neutrophils and follicular center cells are often found in the background of the smear.[19
Rosai–Dorfman disease: Summary of 49 cases with fine needle aspiration
Misdiagnosis of RDD can be rendered in both FNA and surgical biopsy specimens. When compared to surgical core or excisional biopsy, FNA can at times be misinterpreted due to limited or non-representative sampling and, as FNA does not permit examination of the tissue architecture, diagnosis can be further confounded. Despite these potential limitations, FNA is still a very useful tool for the diagnosis of RDD. In fact, emperipolesis, the hallmark for RDD, tends to be more prominent in FNA material than on tissue sections. This is believed to be due, in part, to the fact that in FNA smears, an entire cell may be observed by focusing through the different planes of the slide, whereas in surgical pathology sections, generally a single plane of tissue is available for review. Furthermore, the physical action of spreading the sample into a smear of single cells renders the cellular borders of histiocytes more clearly defined and, thereby, emperipolesis may be more readily and definitively identified. It is important to note, however, that the occurrence of emperipolesis per se should not be considered diagnostic of RDD. Instead, diagnosis requires correlation of the appropriate clinical presentation with an adequately preserved and properly prepared FNA sample of consistent cytomorphologic features. In addition, numerous other disease states either demonstrate emperipolesis or represent cytomorphologic mimics, including lymphoma, malignancy, hemophagocytic syndrome, infection, Langerhans histiocytosis and various other reactive processes .
Figure 2 Emperipolesis in other disorders. Acute and chronic cervicitis. Endocervical cells with indigested neutrophils, cervical smear (a). Endometrial adenocarcinoma tissue fragment with intracytoplasmic lymphocytes and neutophils, cervicovaginal smear (b). (more ...)
Significantly, misdiagnosis of RDD by FNA more often occurs in extranodal rather than in nodal disease. In the cases with biopsy confirmation , 3 out of 25 (12%) lymph node aspirations were misdiagnosed or inconclusive and 6 out of 12 (50%) extranodal aspirations were misdiagnosed. Therefore, in the case where extranodal RDD is suspected, careful clinical lymph node examination should be undertaken and FNA performed in order to maximize diagnostic accuracy. Finally, as RDD is infrequently suspected clinically and is a rare disease process, an awareness of the entity along with its clinical profile is essential in proper specimen evaluation, interpretation and diagnosis.