1 Introduction

Rosai–Dorfman–Destombes disease (RDD) was initially described by Pierre-Paul Destombes in 1965. It is regarded as a rare form of non- Langerhans cell histiocytosis. Early clonality studies have shown it to be polyclonal, and although it is widely accepted to be reactive in nature, its initial status of "presumed to be non-neoplastic", has been challenged recently. Somatic mutations in the mitogen-activated protein kinase (MAPK) pathway found in acquired tissues from a subset of RDD cases suggest at least in some form of RDD a neoplastic origin. Adding to the evolving and enigmatic nature of RDD, important recent studies, in RAS- RAF-MEK-ERK signaling pathway mutations linked to RDD histiocytosis, are suggesting that in certain cases, the illness may be clonal. These recent findings carry equally important diagnostic, classification, and therapeutic implications.¹

Lymph nodes are the most commonly involved organs, although any organ can be involved with RDD. It has a predilection for children and young adults and usually presents with Massive, painless cervical lymphadenopathy (classical nodal involvement) with or without fever, night sweats, and weight loss. Any other lymph node can be involved. Over 40 % of patients exhibit extranodal involvement, and rarely this extranodal involvement occurs in the absence of nodal disease. Most significant extranodal involvement includes hematologic manifestations that occur in 67 % of cases, skin is involved in 10 %, whereas head and neck involvement including the nasal cavity and paranasal sinuses occurs in 11 % of cases. Central nervous system (CNS) involvement occurs in <5 % of cases and bone involvement occurs in 5 %. Primary bone involvement without lymphadenopathy (nodal involvement) is even rarer.²

The mainstay of diagnosis is still immunohistochemistry, which shows S100 and CD68 positive cells and CD1a negative histiocytes. Histopathologically, RRD shows the classical characteristic finding of emperipolesis.³ Up to 50 % of the cases are self-limiting and don't require treatment, however; a very wide scope of treatment is described in the literature, corresponding to the multitude of organ involvement with varying severity. Bone involvement is usually treated with curettage and bone grafting or cementing. Rarely marginal resection is needed. Adjuvant therapy can be considered postoperatively.³ Here, we present a rare case of primary extranodal tibial bone involvement in Rosai Dorfman Disease without any nodal involvement treated with surgery and adjuvant radiotherapy.

2 Case presentation

The patient was a 52-year-old female, known to have asthma, depression, obesity with a body mass index (BMI) of 29 Kg/m², and cervical disc prolapse treated conservatively. She had multiple drug allergies to Tetracycline, Metroidonazole, Diclofenac, and Ibuprofen in the form of skin rash and fever only. She was on her usual well-being status when she started to have right proximal leg pain early in 2018. Her pain started suddenly and increased with time with no preceding trauma or relevant infectious/inflammatory illness. Initially, she was seen in primary health care and treated symptomatically. Her pain did not respond well to analgesics. Following her initial complaints of 10 months, she was presented to our institution with the same proximal tibia pain that had increased significantly in severity and was associated with soft tissue swelling. Upon examination, she was found to be vitally stable, and afebrile, with no enlarged lymph nodes, abdominal pain, or organomegaly. She displayed unremarkable chest and cardiovascular examinations. Her systemic review was negative apart from her local proximal tibia pain and swelling.

Laboratory findings were as follows; White blood cell count (WBC 5.63) (Normal = 3.9–11 μL), (hemoglobin (Hb) 23.5) (Nnormal = 11–16 g/dL), (platelet 258) (Normal = 100–450 x10∗3/μL), (Vitamin B12: 419) (Normal = 138.00–652.00 pmol/l), (ferritin 18.9) (Normal = 10.00–204.00 μg/l), (estimated sedimentation rate (ESR) 21) (Normal = 0–30 mm/H), (lactate dehydrogenase (LDH) 177) (Normal = 125.00–220.00 U/L), and (absolute neutrophil count (ANC) 3.1) (Normal= >1.35-<7.50 10∗3/μL). Negative tests were found for Human immunodeficiency virus (HIV) serology, Human papillomavirus (HPV), Hepatitis C virus (HCV), and Hepatitis B virus (HBV). She had a normal pulmonary function test, but Cytomegalovirus (CMV) was high; (IgG 80.5) (Normal = 0–11.9), (normal IgM: <5) (Normal = 0–17.99), and Epstein Barr Virus (EBV) was high (IgG 27.1) (Normal= <20), and negative IgM (Normal = 1–19.9).

The radiological investigations, included X-ray, computed tomography (CT), and magnetic resonance imaging (MRI). The initial radiographs showed an ill-defined lytic lesion involving the proximal tibia with a rather wide zone of transition (Fig. 1). Computed tomography (CT) showed a solitary eccentric osteolytic lesion involving the anterior tibial tuberosity, measuring 2.7 × 1.5 cm, and exhibiting ill-defined non-sclerotic borders (Fig. 2). MRI showed a locally aggressive solitary eccentric lobulated lesion involving the proximal tibia (Fig. 3). It showed an intermediate - high T1 signal and a high T2 signal. The lesion measures 3.1 x 2.6 × 5 cm in the maximum transverse, AP, and CC dimensions. There is a surrounding bone marrow edema and periosteal edema. Post-contrast administration shows diffuse homogenous enhancement. CT abdomen, pelvis, and chest, and a bone scan confirmed the presence of only tibial bone involvement. Whole body 18F-FDG.

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Fig. 1 Radiological investigation.

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Fig. 2 Computed tomography.

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Fig. 3 Magnetic resonance imaging.

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PET/CT imaging showed only the right focal proximal tibial lesion with a Maximum standardized uptake value (SUV-max) of 14.7 (Fig. 4).

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Fig. 4 Bone scan.

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The patient underwent an ultrasound-guided core biopsy which confirmed the diagnosis by showing mixed inflammatory infiltrates with prominent components of large foamy histiocytes as well as lymphocytes and plasma cells. Some histiocytes contain intracytoplasmic lymphocytes/plasma cells " emperipolesis". The large histiocytes are Positive for CD68 & S100 and Negative for CD1A.

Surgery was done after that, in the form of intralesional curettage and bone cementing with prophylactic fixation with plate and screws. Postsurgical adjuvant radiotherapy was decided at Tumor Board Meetings. We proceeded with administering 36 Gy in 18 fractions in the course of two months with no complications encountered. Follow-up over the span of five years after the surgery and radiotherapy, consisting of regular X-rays (Fig. 5), bone scan, and CT scan of the knee (Fig. 6), showed complete remission with no residual disease or recurrence. Also, the disease did not disseminate. The patient did not need any further surgical or medical intervention for this specific clinical entity. CT displayed surgical resection and cementing of the previously noted locally aggressive lesion centered at the tibial tuberosity. There was an internal fixation with the plate and multiple screws. The hardware was intact. There was no lucency around the cement. There was persistent cortical breakthrough anteriorly with cement extrusion. There was no definite extraosseous enhancing soft tissue component. There were no definite CT features to suggest residual or recurrence (Fig. 6). After 18 months of surgery, an X-ray showed intact hardware with no complications or evidence of recurrence with integrated bone cement (Fig. 7)

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Fig. 5 post-operative x rays.

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Fig. 6 CT scan at follow-up (in June 2018).

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Fig. 7 X-ray at one year of follow-up (18 months following surgery).

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3 Discussion

RDD is characterized by an acquired, idiopathic, nonmalignant proliferation of distinctive histiocytes. The pathological findings of RDD are characterized by the proliferation of a huge number of histiocytes containing abundant eosinophilic cytoplasm, entangled in a variably cellular mixed inflammatory infiltration composed of plasma cells, lymphocytes, neutrophils, foamy macrophages, and rare eosinophils. The characteristic trait of the large histiocytes in RDD is conspicuous emperipolesis-namely lymphocyte-phagocytosis-with intracytoplasmic lymphocytes, plasma cells, or neutrophils.^1,2 The etiology of RDD is still unknown. Infectious causes—including human herpes virus, parvovirus B19, and Epstein-Barr virus—have all been proposed in its etiology but with conflicting experimental results.⁴

Painless, massive, bilateral, symmetric, cervical, and paratracheal lymphadenopathy associated with the systemic symptoms (fevers, pain, tenderness, malaise, night sweats, and weight loss) represents the most common clinical finding. Axillary, para-aortic, inguinal, and mediastinal lymph nodes are also commonly affected. Bone marrow which can be mistaken for chronic osteomyelitis,⁵ liver, and spleen are usually spared.^2,4

Besides involving the lymph nodes, about 45 % of cases had at least one site of extranodal involvement. About 20–25 % of cases had extranodal involvement only. The most frequently affecting extranodal sites are skin, soft tissue, nasal cavity, and paranasal sinuses (16 %); eye, orbit, and bone (11 %), salivary gland, and central nervous system (7 %) and significantly rarer, the oral cavity, kidney, respiratory tract, liver, tonsil, breast, gastrointestinal tract, and heart. Whether it is a nodal and/or extranodal involvement, RDD is often underdiagnosed because of a low index of suspicion of this disease.^2,6

Bone involvement in RDD occurs in 5 %–10 % of cases.⁷ The zone of transition may vary from narrow to wide.⁸ The disease shows a slight predilection for females.⁹ Aside from the craniofacial bones, the disease most commonly arises in the long bones of the appendicular skeleton, with the proximal tibia as the most common location. Other common locations include the spine, pelvis, and tarsal bones.^6,9 Rare cases with involvement of the sacrum, ribs, clavicle, sternum, scapula, patella, carpal bones, and phalanges have all been reported. The lesions are intramedullary and centered in the metaphysis, with some examples showing epiphyseal extension.^6,10 Diaphyseal lesions are less common.^11,12 Pain and swelling of the affected area are the most common presenting symptoms, but the lesions may be asymptomatic.

On imaging, RDD of bone usually presents as intramedullary lytic lesions with well-defined and usually sclerotic margins.^6,9 The lesions may also be mixed lytic and sclerotic.^6,13 Purely sclerotic lesions are rare,¹⁰ with subcutaneous multinodular disease can be detected on FDG PET/CT.¹⁴

Keeping in mind that, RDD has non-specific imaging manifestations that even can minim primary bone tumors of infections such as osteomyelitis, metastatic bone diseases, Langerhans cell histiocytosis, or even giant cell tumors.⁸

Radiographic sclerosis has been described in healing lesions.⁶ Multiloculation with sclerotic internal septations, periosteal reaction, cortical thickening, expansile deformity, and cortical destruction with soft tissue extension may occur, suggesting a locally aggressive form or a malignant bone tumor were could look like lymphoma and malignant fibrous histiocytoma¹⁵ that needs to be ruled out.^6,10–12 On magnetic resonance imaging, the lesions usually show well-demarcated borders and have heterogeneous intermediate to low signals on T1-weighted images and bright signals on T2-weighted images.^10,13 On bone scan, the lesions demonstrate increased radiotracer uptake, which is very helpful for the diagnosis of multifocal lesions.^10,13 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.^16,17

Genetic studies on recently identified mutations in patients with RDD, including BRAF V600E and the nuclear expression of cyclin D1 mutations, may be used to aid in narrowing the differential diagnoses.¹⁸

The mainstay of treating symptomatic bony lesions is surgical excision. It is usually in the form of intralesional curettage and bone grafting or cementing. Adjuvant radiotherapy can be used, and it is thought to reduce recurrence.⁶ Local recurrence is reported to occur after surgery alone. In a reported case of isolated femoral involvement that was treated with surgery alone, in the form of curettage and allograft bone application without adjuvant radiotherapy, recurrence happened after 10 months. Whether, adjuvant radiotherapy confers an additional benefit in reducing recurrence, or not, remains to be further elucidated. It is thought that adjuvant radiotherapy has imparted an additional benefit of reducing the recurrence and dissemination in the case we reported, and that was the basis of its use here. Therapeutic Modalities like corticosteroids, immunosuppressive therapy, and chemotherapy are not used routinely for isolated bony involvement of RDD.^3,19 Keeping in mind, that the disease course and prognosis are not well defined but the overall outcome seems to be good.⁸ Given the fact that recurrence and dissemination can happen after surgical treatment of isolated bony involvement of RDD, follow-up and surveillance are advised with detailed instructions provided to the patient about when to visit the clinic or seek any medical attention.

4 Conclusion

Rosai-Dorfman disease (RDD) is extremely uncommon disease, which characterised by histiocytes in the lymph nodes or it can be extranodal. Clinial features and area of involvement in body can be different from case to case. Investigations usually include labs, imaging and biopsy if needed. Management generally varies based on clinical and investigation findings which include observation, surgical and radiation therapy.

CRediT authorship contribution statement

Abdullah F. Alotaibi: Acquistion, Formal analysis, Drafting og manuscript, Critical review of the manuscript for importan intellectual content. Talal Alrawaf: Acquistion, Formal analysis, Drafting og manuscript. Osama Alshaya: Concept and design, Critical review of the manuscript for importan intellectual content. Hassan Sawan: Concept and design. Muath Aljufayr: Acquistion, Formal analysis, Drafting og manuscript.

Human subjects

Consent was obtained by the patient in this case.

Informed consent

Verbal informed consent was obtained for anonymized patient information to be published in this article.

Ethics approval

Ethical approval for this study/case/case series was obtained from IRB Board of King Fahad Medical City (APPROVAL NUMBER: FWA00018774).

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.