Authors: Abdelilah Rguyeg, Mohamed Boutahar, Azeddine Lachkar
Categories: Case Report, Rosai–Dorfman disease, Cervical lymphadenopathy, Histiocytosis, Emperipolesis, Surgical management
Source: Radiology Case Reports
Authors: Abdelilah Rguyeg, Mohamed Boutahar, Azeddine Lachkar
Rosai–Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic disorder most commonly involving the cervical lymph nodes, which are affected in approximately 80%-90% of cases. It predominantly affects children and young adults but may occur at any age, typically presenting with painless, bilateral, and sometimes bulky cervical lymphadenopathy, occasionally associated with systemic inflammatory symptoms and laboratory abnormalities such as elevated inflammatory markers and polyclonal hypergammaglobulinemia. Histopathological examination is essential for diagnosis and demonstrates marked sinus expansion by large histiocytes with abundant pale cytoplasm and characteristic emperipolesis, set within a lymphoplasmacytic background. Immunohistochemically, these histiocytes express CD68, CD163, and S100 protein, while lacking CD1a and langerin expression, allowing distinction from other histiocytic disorders. Although historically considered a benign reactive condition, recent molecular studies have identified activating mutations in the MAPK/ERK signaling pathway, including KRAS, NRAS, and MAP2K1, in a significant subset of cases, supporting a clonal neoplastic component. The clinical course of cervical RDD is generally favorable, and management is individualized, ranging from observation to surgical excision in cases of compressive symptoms, with systemic or targeted therapies reserved for refractory or multisystem disease.
We report the case of a 25-year-old patient with no significant past medical history who presented with a persistent cervical lymphadenopathy. Comprehensive clinical evaluation, laboratory investigations, and imaging studies supported the diagnosis of Rosai–Dorfman disease. Prompt recognition and appropriate surgical management play a crucial role in achieving favorable clinical outcomes.
Rosai–Dorfman disease, also referred to as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic disorder characterized by the accumulation of distinctive histiocytes exhibiting emperipolesis. First described in the late 1960s, RDD classically presents with painless, bilateral cervical lymphadenopathy and predominantly affects children and young adults, although cases have been reported across all age groups. Despite its generally benign course, the clinical presentation of RDD is heterogeneous, ranging from isolated nodal disease to multifocal extranodal involvement [1].
Cervical lymph node involvement represents the most common and prototypical manifestation, occurring in up to 80%-90% of patients. The disease may be accompanied by systemic inflammatory symptoms such as fever, weight loss, and night sweats, as well as laboratory abnormalities including elevated inflammatory markers and polyclonal hypergammaglobulinemia. Radiological findings are often nonspecific, and the differential diagnosis is broad, encompassing infectious, inflammatory, and malignant lymphoproliferative disorders, which may delay diagnosis [2].
Histopathological examination remains the cornerstone of diagnosis, revealing dilated lymph node sinuses infiltrated by large histiocytes with abundant pale cytoplasm and characteristic emperipolesis, supported by a distinctive immunophenotype. Recent advances in molecular pathology have identified activating mutations in the MAPK/ERK signaling pathway in a subset of cases, challenging the traditional view of RDD as a purely reactive process. Early recognition of cervical RDD is essential to guide appropriate management, avoid unnecessary aggressive treatments, and ensure favorable clinical outcomes [3].
A 25-year-old patient with no significant past medical history and no personal or family history of tuberculosis presented to our outpatient clinic with a progressively enlarging midline cervical swelling. The clinical presentation was associated with general malaise and an unintentional weight loss of approximately 5 kg over the preceding two weeks. No other systemic symptoms were reported.
On physical examination, the patient was mildly febrile with a body temperature of 37.5°C. Palpation of the neck revealed a single submental cervical lymph node that was mobile, well circumscribed, and mildly tender, without pain on palpation or signs of overlying skin inflammation. No additional lymphadenopathy or organomegaly was detected, and the remainder of the general physical examination was unremarkable.
Laboratory investigations included a complete blood count, tuberculin skin test, serum lactate dehydrogenase (LDH) level, liver function tests, and serological testing for toxoplasmosis, Bartonella henselae, mumps virus, and Epstein–Barr virus. All investigations were within normal limits except for leukocytosis (total leukocyte 25,000 cells/mm³) with predominant lymphocytosis, and a markedly elevated LDH level of 1200 U/L. Although LDH elevation may raise suspicion for lymphoproliferative malignancy, it remains a non-specific marker of cellular turnover and requires histopathological confirmation for definitive diagnosis.
All results were within normal limits except for leukocytosis (total leukocyte 25,000 cells/mm³) with predominant lymphocytosis, and a markedly elevated LDH level of 1200 U/L. Although markedly elevated LDH levels are often associated with lymphoma, LDH is a non-specific marker of cellular turnover and does not establish malignancy without histopathological confirmation.
Cervical ultrasonography demonstrated a well-defined, oval hypoechoic lymph node measuring 49 × 29 mm in the submental region (Fig. 1). The node preserved an oval morphology with a long-to-short axis ratio greater than 2 and showed increased cortical thickness (maximum cortical X mm). The fatty hilum was partially effaced. No central necrosis, calcification, or cystic changes were identified. Color Doppler evaluation demonstrated predominantly hilar vascularity without abnormal peripheral neovascularization.Fig. 1Ultrasound image demonstrating an enlarged midline submental cervical lymph node with cortical thickening, measuring 49 × 29 mm.Fig 1 dummy alt text
Given the combination of cervical lymphadenopathy, systemic symptoms, lymphocytosis, and elevated LDH levels, the main differential diagnoses considered were non-Hodgkin lymphoma and, to a lesser extent, tuberculous lymphadenitis. Consequently, an excisional lymph node biopsy was performed to obtain definitive histopathological diagnosis (Fig. 2, Fig. 3).Fig. 2Intraoperative photograph showing the excisional lymphadenectomy performed under general anesthesia.Fig 2 dummy alt textFig. 3Gross specimen showing the resected cervical lymphatic chain following lymphadenectomy.Fig 3 dummy alt text
Histopathological examination of the cervical lymph node biopsy demonstrated a diffuse proliferation of large histiocytes with abundant pale cytoplasm, admixed with a dense polymorphous inflammatory infiltrate rich in plasma cells and lymphocytes. Numerous histiocytes exhibited prominent emperipolesis (Fig. 4). Immunohistochemical analysis showed strong expression of histiocytic markers, including CD68, CD163, and S100 protein. In contrast, the histiocytes were negative for CD1a and langerin (CD207), thereby excluding Langerhans cell histiocytosis and supporting the diagnosis of Rosai–Dorfman disease.Fig. 4Hematoxylin and eosin staining showing large histiocytes with abundant pale cytoplasm and prominent emperipolesis (black arrows), within a polymorphous lymphoplasmacytic background.Fig 4 dummy alt text
Taken together, these immunohistochemical findings confirmed a non–Langerhans cell histiocytic proliferation. The combined morphologic features, including abundant histiocytes with prominent emperipolesis, and the characteristic immunophenotype with strong CD68, CD163, and S100 expression in the absence of CD1a and langerin (CD207), are highly consistent with the diagnosis of Rosai–Dorfman disease. This profile effectively excludes other histiocytic disorders and supports the definitive pathological diagnosis in the appropriate clinical context.
Given the primary form of the disease, and following a multidisciplinary discussion involving internal medicine specialists and otorhinolaryngology surgeons, a conservative medical approach was adopted. Treatment was initiated with systemic corticostotherapy using prednisolone at a dose of 1 mg/kg/day, followed by a gradual taper over a total treatment duration of four weeks. This regimen was combined with analgesic therapy consisting of paracetamol at a dose of 1 g every 8 hours for ten days. The clinical response was favorable, with complete resolution of systemic symptoms and normalization of lymphocyte counts and serum lactate dehydrogenase levels observed two months after diagnosis. The patient remained asymptomatic with no evidence of recurrence during an eight-month follow-up period.
Rosai–Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-Langerhans cell histiocytic disorder characterized by the accumulation of distinctive histiocytes showing emperipolesis. Initially described as a benign and self-limited reactive condition, RDD is now recognized as a heterogeneous disease entity with variable clinical behavior, ranging from isolated nodal involvement to multisystem disease. Cervical lymphadenopathy represents the classic and most frequent manifestation, often posing diagnostic challenges due to its clinical overlap with malignant and infectious disorders [4].
RDD predominantly affects children and young adults, with a slight male predominance reported in most series, although cases can occur at any age. Cervical lymph node involvement is observed in approximately 80%-90% of patients and often constitutes the initial presentation. Extranodal involvement is reported in up to 40%-50% of cases, frequently affecting the head and neck region, skin, orbit, and upper respiratory tract. The disease appears to be more prevalent in individuals of African descent, although this distribution may reflect reporting bias [5].
The pathogenesis of RDD remains incompletely understood. Historically considered a reactive inflammatory process, recent molecular studies have demonstrated activating mutations in the MAPK/ERK signaling pathway, including KRAS, NRAS, and MAP2K1, in a significant subset of cases, supporting a clonal histiocytic proliferation. These findings have led to the reclassification of RDD as a histiocytic neoplasm in contemporary classifications. Immune dysregulation, infectious triggers, and associations with autoimmune diseases have also been proposed, although no definitive causative factor has been identified [6].
The positive diagnosis of Rosai–Dorfman disease is based on the integration of clinical presentation, laboratory findings, imaging features, and, most importantly, histopathological and immunohistochemical confirmation. Clinically, cervical lymphadenopathy represents the hallmark manifestation and is typically characterized by painless, slowly enlarging lymph nodes that may be unilateral or bilateral. Although classically described as asymptomatic, cervical RDD may be associated with systemic symptoms such as fever, fatigue, malaise, and unintentional weight loss, reflecting an underlying inflammatory process. In the present case, the combination of persistent cervical lymphadenopathy and recent constitutional symptoms raised early concern for a malignant or infectious etiology [7].
Paraclinical biological findings in RDD are nonspecific but frequently supportive. Common laboratory abnormalities include elevated inflammatory markers, polyclonal hypergammaglobulinemia, anemia of inflammation, leukocytosis, or lymphocytosis, as well as increased serum lactate dehydrogenase (LDH) levels. These abnormalities may mimic those observed in lymphoproliferative disorders, thereby contributing to diagnostic uncertainty. In our patient, marked lymphocytosis and a significantly elevated LDH level reinforced the initial suspicion of lymphoma and justified further invasive diagnostic workup [8].
Imaging plays an important adjunctive role in the diagnostic process, primarily for lesion characterization, assessment of disease extent, and exclusion of alternative diagnoses. Cervical ultrasonography typically demonstrates well-circumscribed, oval hypoechoic lymph nodes that may preserve an oval morphology and lack central necrosis, although these findings remain non-specific.
Although cross-sectional imaging was not performed in this case due to localized disease and immediate biopsy planning, computed tomography typically demonstrates homogeneous lymph node enlargement without central necrosis or calcifications. Magnetic resonance imaging may reveal iso-to-hypointense signal intensity on T1-weighted images and mild hyperintensity on T2-weighted images, with homogeneous post-contrast enhancement. These imaging features, while not pathognomonic, may help exclude necrotic infectious adenopathy or metastatic lymph node disease and guide appropriate biopsy planning [9].
From a radiological standpoint, ultrasound-guided core needle biopsy represents a minimally invasive diagnostic alternative that may provide sufficient tissue for histological and immunohistochemical analysis in selected cases. However, when lymphoma or atypical lymphoproliferative disorders are strongly suspected, excisional biopsy remains the gold standard, as it allows complete architectural evaluation of lymph node sinuses and ensures definitive diagnosis.
Definitive diagnosis relies on histopathological examination of an excisional lymph node biopsy. Characteristic features include dilated lymph node sinuses infiltrated by large histiocytes with abundant pale cytoplasm and round to oval nuclei, admixed with a polymorphous inflammatory infiltrate rich in lymphocytes and plasma cells. The presence of emperipolesis—intact lymphocytes or plasma cells within the cytoplasm of histiocytes—represents a key diagnostic hallmark, although it may be focal or absent in some cases. Immunohistochemical analysis is essential and typically demonstrates strong expression of CD68, CD163, and S100 protein by the histiocytes, with negativity for CD1a and langerin (CD207), thereby excluding Langerhans cell histiocytosis. In the appropriate clinical context, this distinctive morphologic and immunophenotypic profile establishes the diagnosis of RDD with a high degree of certainty.
The differential diagnosis of isolated cervical lymphadenopathy in young adults is broad and includes infectious, malignant, and metastatic etiologies. Infectious causes, particularly tuberculous lymphadenitis, typically demonstrate central necrosis, peripheral rim enhancement on contrast-enhanced CT, and nodal matting. Calcifications may be observed in chronic stages. Malignant causes, especially non-Hodgkin lymphoma, often manifest as multiple rounded lymph nodes with loss of the fatty hilum, homogeneous soft-tissue attenuation, and possible conglomerate nodal masses. Despite homogeneous enhancement, lymphoma usually presents with more diffuse nodal involvement. Metastatic lymphadenopathy may show central necrosis, irregular borders, capsular disruption, and signs of extracapsular spread. These features are particularly suggestive in patients with known primary malignancy. In contrast, Rosai–Dorfman disease typically presents with homogeneous lymph node enlargement without necrosis or calcification, although imaging findings remain non-specific. Therefore, histopathological confirmation remains essential for definitive diagnosis [10].
There is no standardized therapeutic strategy for RDD, and management should be individualized based on disease extent, symptom severity, and organ involvement. Asymptomatic or localized nodal disease may be managed conservatively with observation alone. Corticosteroid therapy was initiated in our patient due to symptomatic disease and systemic inflammatory features, including constitutional symptoms and biological abnormalities. While isolated nodal RDD may be observed in selected cases, systemic therapy is recommended in symptomatic patients. Surgical excision is primarily indicated for diagnostic purposes or in cases of compressive symptoms. In our case, short-term systemic corticosteroid therapy resulted in complete clinical and biological remission [11].
The overall prognosis of RDD is generally favorable, especially in cases of isolated cervical lymphadenopathy. Spontaneous remission has been reported, and disease-related mortality is rare. Poor prognostic factors include extensive extranodal involvement, vital organ compression, and association with immune or neoplastic disorders. In our patient, early diagnosis and appropriate medical management resulted in complete clinical and biological remission, with no recurrence observed during follow-up. Long-term surveillance remains recommended due to the potential for relapse or progression [12].
This case highlights the importance of imaging in the initial evaluation of persistent cervical lymphadenopathy. Although radiological findings are often non-specific, ultrasound plays a crucial role in lesion characterization and guiding biopsy. Awareness of Rosai–Dorfman disease among radiologists may help narrow the differential diagnosis and avoid unnecessary aggressive interventions.
The patient gave their informed consent to the publication of this case report.