Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown pathogenesis that may be diagnostically difficult in extranodal sites. It is commonly an unsuspected diagnosis when arising in bone and soft tissue, especially when it presents without associated lymphadenopathy. Its variable clinical presentation and nonspecific imaging findings make the diagnosis quite challenging, particularly in small biopsies. The problem is compounded by its less-characteristic histomorphologic features in comparison with nodal disease. Awareness of the potential diagnostic pitfalls in Rosai-Dorfman disease of bone and soft tissue should raise the degree of diagnostic accuracy.
To review the clinical manifestations, imaging characteristics, and histomorphologic features of Rosai-Dorfman disease of bone and soft tissue along with a brief discussion of its differential diagnosis, pathogenesis, and current management.
Thorough review of the literature with focus on clinical manifestations, imaging findings, key histomorphologic features, pathogenesis, and treatment.
The diagnosis of Rosai-Dorfman disease of bone and soft tissue may be quite challenging because of its variable clinical presentation and nonspecific imaging findings. It may be asymptomatic without systemic manifestations or associated lymphadenopathy. The definitive diagnosis relies on histopathologic identification of the characteristic S-100–positive histiocytes demonstrating emperipolesis. Bone and soft tissue lesions tend to have lower numbers of characteristic histiocytes and less conspicuous emperipolesis and often demonstrate areas of fibrosis or storiform spindle cell areas resembling fibrohistiocytic lesions. Awareness of these unusual features is necessary in order to consider Rosai-Dorfman disease in the differential diagnosis when confronting these rare and often misleading lesions.
Rosai-Dorfman disease (RDD) is a rare disorder of uncertain pathogenesis characterized by a proliferation of large histiocytes with distinctive intact intracytoplasmic leukocytes (emperipolesis) and a variable mixed inflammatory infiltrate. The lesion was first described as “adenitis with lipid excess”1 and formally characterized later as “sinus histiocytosis with massive lymphadenopathy.”2,3 The original descriptions were in lymph nodes of pediatric and young adult patients who presented with painless bilateral cervical lymphadenopathy. Further recognition of this condition led to its diagnosis in numerous extranodal sites, including skin, subcutaneous tissue, deep soft tissue, bone, head and neck, visceral organs, central nervous system, breast, thyroid, salivary glands, mesentery, and retroperitoneum.4–7 Extranodal RDD comprises 43% of all cases. The lesion has been described at practically any age.5 The clinical presentation may be quite heterogeneous, with single or multifocal nodal disease, mixed nodal and extranodal disease, or pure extranodal disease without evidence of lymph node involvement.5 Systemic symptoms may include fever, leukocytosis, elevated erythrocyte sedimentation rate, anemia, weight loss, and polyclonal hypergammaglobulinemia.2,3,5 The histopathologic diagnosis of RDD may be quite challenging when it arises in bone and soft tissue, where the histomorphologic features may not be as characteristic and the condition is usually unsuspected, especially in the absence of lymphadenopathy. The lesions may look aggressive on imaging and often mimic other disease processes such as infection or Langerhans cell histiocytosis (LCH) as well as various benign and malignant tumors of bone, which represents a treacherous diagnostic pitfall.8–22 Therefore, it is important to recognize the main clinical, radiologic, and pathologic features of this condition when it presents as primary bone or soft tissue disease in order to ascertain a correct diagnosis and ensure proper management.
CLINICAL AND RADIOLOGIC FEATURES
RDD of Bone
Bone involvement by RDD occurs in 5% to 10% of cases.5 The disease shows a slight predilection for females. The mean age is 31 years.23 Aside from the craniofacial bones, the disease most commonly occurs in the long bones of the appendicular skeleton, with the proximal tibia being the most common location. Other common locations include the spine, pelvis, and tarsal bones.16,23,24 Rare cases with involvement of the sacrum, ribs, clavicle, sternum, scapula, patella, carpal bones, and phalanges have been reported.* The lesions are intramedullary and centered in the metaphysis, with some examples showing epiphyseal extension.16,25 Diaphyseal lesions are less common.11,13,22,24 Pain and swelling of the affected area are the most common presenting symptoms, but the lesions may be asymptomatic.16 Rosai-Dorfman disease of bone is most often multifocal,8,13,17,24,26,27 but it may present as a solitary lesion.† Both presentations may occur with or without associated lymphadenopathy.‡ Concomitant involvement of other extranodal sites such as soft tissue, paranasal sinuses, central nervous system, and orbit is not uncommon in skeletal RDD.23,24,27
Radiographically, RDD of bone usually presents as intramedullary lytic lesions with well-defined and usually sclerotic margins (Figure 1, A).8,16 The lesions may also be mixed lytic and sclerotic (Figure 1, B).12,16 Purely sclerotic lesions are rare.25 Radiographic sclerosis has been described in healing lesions.16,27 Multiloculation with sclerotic internal septations, periosteal reaction, cortical thickening, expansile deformity, and cortical destruction with soft tissue extension may occur, suggesting a locally aggressive or malignant bone tumor.10,13,16,21,22 On magnetic resonance imaging, the lesions usually show well-demarcated borders and have heterogeneous intermediate to low signal on T1-weighted images and bright signal on T2-weighted images (Figure 1, C and D).10,–12,17,20,30 On bone scan, the lesions demonstrate increased radiotracer uptake, which is very helpful for the diagnosis of multifocal lesions.10,17,27 The lesions are hypermetabolic on positron emission tomography–computed tomography, which is another useful modality for the detection of multifocal asymptomatic lesions and evaluation of treatment response.20,30–32 Whole-body diffusion-weighted magnetic resonance imaging has also been used to detect multifocal bone disease and to evaluate response to therapy without the need for radiation or intravenous contrast agents.33
RDD of Soft Tissue
In the soft tissues, RDD more commonly involves the subcutaneous adipose tissue and less commonly the deep soft tissue.5,6,18,19,30 Subcutaneous lesions may extend to the overlying reticular dermis.6 Red-brown skin discoloration has been described in subcutaneous lesions with dermal involvement.34,35 The most common presentation is as a slow-growing, painless mass in the extremities, trunk, head and neck, or retroperitoneum.6,19 Some studies report a rapid evolution of the lesions.36–38 Pain may occur in 16.8% of cases.18 Rosai-Dorfman disease of soft tissue tends to arise in older age than classic nodal disease, with a mean age of 42.5 to 46 years, and demonstrates female predilection.6,36 It may present as a single or multiple lesions with or without associated lymphadenopathy.6,35,36,39,40 Lymph node involvement is reportedly uncommon in soft tissue RDD.6,35,36,40 The lesions are often well demarcated but sometimes may have ill-defined margins and range from 0.5 to 13.7 cm in size (median, 2.4 cm).36 The imaging characteristics of RDD of soft tissue are not specific but may be suggestive of a sarcoma. On computed tomography, the lesions appear as ill-defined masses that are isodense to muscle and demonstrate homogeneous enhancement after contrast administration.30 On magnetic resonance imaging, RDD of soft tissue is usually isointense to muscle on T1-weighted images and hyperintense on T2-weighted and short tau inversion recovery images. Heterogeneous postcontrast enhancement is seen.30,35,37,38 The lesions are hypermetabolic on positron emission tomography–computed tomography, which facilitates their detection.30,41
The definitive diagnosis of RDD relies on histopathologic confirmation and identification of the typical proliferating histiocytes. Classic nodal disease is characterized by effacement of lymph node architecture with conspicuous dilatation and expansion of the sinuses by a population of numerous distinctive large histiocytes demonstrating emperipolesis.3,4 The histomorphologic features in bone and soft tissue are very similar to those of nodal disease, except for a greater tendency of the lesions to undergo fibrosis and less conspicuous emperipolesis, which is not specific but quite characteristic of RDD.6,16,24 Macroscopically, bone lesions are soft to gritty with a white to gray-tan color.16 Microscopically, they demonstrate a cellular infiltrate within the marrow spaces composed of large histiocytes and a variable inflammatory infiltrate composed predominantly of lymphocytes and plasma cells (Figure 2, A). The histiocytes are large with abundant pale eosinophilic cytoplasm and display central round to oval vesicular nuclei with distinct and sometimes prominent nucleoli. Intact intracytoplasmic lymphocytes are frequently identified within the large histiocytes (Figure 2, B). Intracytoplasmic plasma cells and neutrophils may also be seen. Mitotic figures are rare. Other distinctive features include the presence of foamy macrophages, clusters of neutrophils resembling microabscesses, foci of fibrosis, and spindle cell areas with a storiform pattern. Eosinophils are rare and usually absent.16,24 Foci of necrosis with granuloma-like arrangement of histiocytes may be seen. The lesions demonstrate permeative growth with osteoclastic resorption of the preexisting trabecular bone.16 Rare radiographically sclerotic lesions may show thickening of the trabecular bone.25 Reactive new bone formation may be seen at the periphery of the lesions, resulting in marked sclerosis.16 Fine-needle aspiration cytology has been used as a reliable and less invasive diagnostic method in cases of primary RDD of bone based on the identification of the large histiocytes with emperipolesis (Figure 2, C).42–45 Soft tissue lesions are grossly poorly circumscribed or may be well demarcated, have firm to indurated consistency, and show a nodular cut surface ranging in color from yellow to ivory-tan to white.6,40 Microscopically, the lesions demonstrate nodular architecture, areas of fibrosis with collagen deposition, spindling of the histiocytes with storiform arrangement, variable lymphoplasmacytic infiltrates, and lymphoid aggregates with germinal centers (Figure 3, A and B). The characteristic histiocytes are polygonal with abundant clear to eosinophilic cytoplasm and display conspicuous emperipolesis (Figure 3, C). The nuclei are round to oval with vesicular chromatin and conspicuous to prominent nucleoli. Occasional multinucleated giant cells, focal neutrophilic microabscesses, and perivascular hyalinization may be seen. Mitoses are rare, and necrosis is uncommon. Regardless of the site of origin of the lesion, the histiocytes of RDD are strongly positive for S-100 protein (Figure 3, D). They also show reactivity for CD68 and CD163. CD1a and langerin are consistently negative, distinguishing the lesion from LCH (see Table).6,16,36
The imaging characteristics of RDD of bone and soft tissue are not specific and are often misleading. Radiographically, bone lesions are often misdiagnosed as osteomyelitis or LCH. Other entities in the differential diagnosis include Erdheim-Chester disease, lymphoma, plasma cell myeloma, and metastatic disease.16 Osteomyelitis is a necrotizing and sclerosing bone disease dominated by inflammation, often including numerous neutrophils and with frequent periosteal reactive bone formation. Bone necrosis, sclerosis, and periosteal reaction are not prominent features in RDD of bone but may rarely occur. Histologically, the mixed inflammatory infiltrate with focal neutrophilic microabscesses, occasional multinucleated giant cells, and granuloma-like histiocyte collections seen in RDD of bone may suggest infection or granulomatous disease. However, the characteristic S-100–positive histiocytes with emperipolesis are not seen in either condition. Special stains and cultures are consistently negative for microorganisms. Langerhans cell histiocytosis may present as unifocal, multifocal, or systemic disease and usually involves the craniofacial bones, long bones, vertebral bodies, ribs, and pelvis. The lesions are usually lytic and well demarcated. Cortical destruction with soft tissue extension and periosteal reaction may occur. Histologically, the lesions are characterized by an inflammatory infiltrate dominated by eosinophils, which are uncommon in RDD. Plasma cells are usually sparse. Langerhans histiocytes are usually disposed in granuloma-like clusters and have characteristic elongated, indented, grooved, or convoluted nuclei with inconspicuous nucleoli. In addition to S-100 protein, they are consistently positive for CD1a and langerin, which are not expressed by RDD histiocytes (see Table). Emperipolesis is not a feature of LCH. Erdheim-Chester disease is a multisystemic proliferative histiocytic disorder characterized by long bone involvement with bilateral and symmetrical sclerotic lesions. Frequently there is extraskeletal involvement including cardiovascular system, central nervous system, kidneys, and lungs. Histologically, there is a proliferation of foamy histiocytes within the marrow spaces with associated fibrosis and thickening of bone trabeculae. Touton-type multinucleated giant cells, lymphocytes, plasma cells, and neutrophils may be present. The proliferating histiocytes are positive for CD163 and CD68 and are usually negative for S-100 (see Table). They are also negative for CD1a and langerin. Emperipolesis is not seen in Erdheim-Chester disease. The heterogeneous and polyclonal cell population of RDD, including B and T lymphocytes, plasma cells, neutrophils, and histiocytes, is sufficient to exclude non-Hodgkin lymphoma and plasma cell myeloma. Hodgkin lymphoma is excluded by lack of CD15 and CD30 immunohistochemical expression by the large histiocytes of RDD and S-100 positivity. Metastatic carcinoma and melanoma can be ruled out by histomorphology and the lack of epithelial and melanocytic marker expression.
On imaging, RDD of soft tissue is often confused with an inflammatory, granulomatous, or neoplastic process including soft tissue sarcoma.18,19 Histologically, the diagnostic features may be obscured by the mixed inflammatory infiltrate along with a lower number of characteristic histiocytes, less conspicuous emperipolesis, the presence of fibrosis, and spindle cell areas with storiform pattern. Identification of the characteristic S-100–positive histiocytes with emperipolesis is very helpful in confirming the diagnosis, but these are often less conspicuous compared with nodal disease. Histologically, the lesions are often confused with a fibrohistiocytic lesion or an inflammatory myofibroblastic tumor.6,18,39 Fibrous histiocytoma is characterized by a proliferation of plump spindle cells with storiform arrangement, multinucleated giant cells, foamy cells, and mild chronic inflammatory infiltrate composed of lymphocytes and plasma cells. Scattered dendritic cells can be detected with factor XIIIA and S-100 protein, but characteristic S-100–positive large histiocytes with emperipolesis are not seen. Inflammatory myofibroblastic tumor is composed of plump spindle cells arranged in a fascicular pattern and a myxoid stroma with variable inflammatory infiltrates including lymphocytes, plasma cells, and eosinophils. The tumor cells invariably express myoid markers (smooth muscle actin, muscle-specific actin, calponin, and desmin) and are positive for keratin in about one-third of cases. ALK-1 is expressed in 50% to 60% of the cases and S-100 is negative.
The etiology of RDD remains uncertain. Proposed mechanisms include immune dysfunction and possible viral infection.46 The association of RDD with immunologic abnormalities has been well established and includes arthritis, glomerulonephritis, amyloidosis, autoimmune hemolytic anemia, and hematologic autoantibodies, among others. They may be predictors of poor outcome.4,46 A viral etiology has been proposed but not clearly established. Serologic evidence of Epstein-Barr virus infection has been described in RDD.46 Human herpesvirus 6 has been detected in a small case series including one soft tissue mass, suggesting a role in the pathogenesis of the disease.47 Parvovirus B19 was reported in another small series including nodal and extranodal cases.48 Polyomavirus antigen was detected in 3 cases of soft tissue RDD.36 A proposed mechanism for RDD is monocyte/macrophage stimulation by macrophage colony-stimulating factor leading to immune suppressive macrophages with increased phagocytosis of lymphocytes. The initiating factor is yet to be elucidated.49,50 Genetic mutations similar to those seen in LCH and Erdheim-Chester disease have been reported in RDD and are summarized in the Table. Mutually exclusive KRAS and MAP2K1 mutations were described in a subset of cases of RDD. KRAS mutation was detected in 1 case arising in soft tissue and 2 cases involving the bones of the skull base. MAP2K1 mutation was detected in one case involving bone.51 Subsequently, another study52 demonstrated cyclin D1 immunohistochemical expression in 86% of cases including bone and soft tissue lesions, reflecting constitutive MAPK pathway activation in the pathogenesis of RDD. These authors proposed that at least a subset of RDD cases are clonal in nature. Germline mutations of the SLC29A gene have been detected in the rare familial form of RDD but not in sporadic cases.53 A subset of RDD cases may show increased numbers of immunoglobulin G4 (IgG4)–positive plasma cells, but a relationship with IgG4-related disease has not been definitively established.54,55 Rosai-Dorfman disease and LCH are distinct clinicopathologic entities, but rare cases with concurrence of both conditions in a single site have been described, including cases involving bone and soft tissue, suggesting a possible relationship between the two.56–58 Furthermore, BRAF-V600E mutations have been detected in such combined cases, suggesting that Langerhans cells and RDD histiocytes may derive from a common precursor.59 One case of nodal RDD with confirmed BRAF-V600E mutation has been reported, representing a promising therapeutic target, especially for patients with refractory or extensive disease.60 Most recently, 3 cases with RDD/Erdheim-Chester disease overlap have been reported, 2 of them harboring MAP2K1 mutations.61
TREATMENT AND PROGNOSIS
Rosai-Dorfman disease of bone and soft tissue with or without lymphadenopathy usually has a good prognosis, with a self-limited course and frequent spontaneous involution of the lesions.5,16,62 Surgical excision (intralesional curettage) is advised for symptomatic bone lesions, whereas asymptomatic lesions may be observed.16 Follow-up or local excision is recommended for soft tissue lesions.62 Local recurrences may occur after surgery.6,41 Steroids, immunosuppressive therapy, chemotherapy, and radiation have been used, depending on the location, extent of disease, and vital organ involvement, but are not standard use in the management of bone and soft tissue lesions. They are indicated in cases of disseminated disease or those refractory to surgical treatment.61–63 Bone involvement has been correlated with worse prognosis, as 3 of 4 fatal cases in the largest series had bone involvement.5 However, the great majority of reported bone lesions have a benign course and favorable prognosis.16 Additional skeletal, extraskeletal, and nodal disease may develop subsequent to the initial diagnosis. Therefore, follow-up and surveillance are advised.16 The association of RDD with immunologic abnormalities such as systemic lupus, idiopathic juvenile arthritis, glomerulonephritis, amyloidosis, and autoimmune hemolytic anemia, among others, may imply greater morbidity and mortality.4,46
The diagnosis of RDD arising in bone and soft tissue may be quite challenging because of its variable clinical manifestations and nonspecific imaging findings that sometimes may be suggestive of malignancy. The disease more commonly affects middle-aged women and may be often asymptomatic without systemic manifestations or associated lymphadenopathy, making the degree of diagnostic suspicion quite low. The definitive diagnosis relies on histopathologic identification of the characteristic histiocytes demonstrating S-100 protein immunoreactivity and emperipolesis. This may be particularly difficult, especially in small biopsies, because bone and soft tissue lesions tend to have lower numbers of characteristic histiocytes and less conspicuous emperipolesis and often demonstrate areas of fibrosis or storiform spindle cell areas. Furthermore, the background mixed inflammatory infiltrate that is often present in these lesions may raise suspicion for infection, lymphoma, or inflammatory myofibroblastic tumor. Awareness of these unusual features is necessary in order to consider RDD in the differential diagnosis when confronting these rare and often misleading lesions. The overall prognosis of RDD of bone and soft tissue is good, as the disease course is often self-limited with frequent spontaneous involution of the lesions. Treatment with surgical excision is reserved for symptomatic lesions. Observation is adequate for patients with asymptomatic localized disease. The pathogenesis of RDD is yet to be elucidated, but recent studies suggest possible clonality.
We would like to thank our colleagues Michael Klein, MD, and Daniel Ramirez, MD, for contributing some of the radiologic and histologic images.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the Seventh Princeton Integrated Pathology Symposium; May 16, 2020; virtual.