Introduction

Rosai-Dorfman disease (RDD) is a rare non-neoplastic histiocytic proliferative disease of non-Langerhans cells of unknown etiology.1,2 Classical ganglionic RDD, in its sporadic, non-cutaneous form, is characterized by massive painless bilateral cervical lymphadenopathy, fever, leukocytosis, weight loss, and elevated erythrocyte sedimentation rate.1,3 It primarily affects children and young adults (average age of onset 20.6 years), with a slightly higher predominance in males (male-to-female ratio of 1:4).1,4

Extranodal involvement occurs in approximately 40% of cases,1-4 usually in older individuals.1,4 Sites of extraganglionic involvement include skin, bones and tissues of the nasal and orbital cavities, bones, central nervous system, gastrointestinal tract, and digestive system.1-5

Bone involvement, usually associated with a good prognosis,2 occurs in less than 10% of patients with extranodal RDD, with an average age of 31.1 years and a slight predilection for women.2,6 After craniofacial bones, the disease mainly affects long bones, particularly the tibia, while other commonly affected sites include the spine, pelvis, and tarsal bones.2,6

Primary extranodal involvement of the bones (known as primary RDD of bone) with no clinically detectable lymph node disease (i.e., lymphadenopathy) is rare and may, both radiologically and clinically, mimic various tumors and infections.7,8 In most cases, primary RDD of bone is multifocal, but it can also present as a solitary lesion. On X-rays, lytic lesions with well-defined sclerotic margins are typically found when there is bone involvement,2,6 but lesions may also be mixed (lytic and sclerotic) or purely sclerotic, although the latter are rare.2

RDD is diagnosed only based on histopathological examination, which indicates a mixed infiltrate composed of histiocytes, lymphocytes, and plasma cells.1,7 Its most distinctive feature is emperipolesis, a phenomenon in which large histiocytes contain intact lymphocytes or plasma cells within the cytoplasm of another cell.1,3,7 Immunohistochemical staining confirms the diagnosis, with histiocytes showing pathognomonic positivity for S100 and CD68 and negativity for CD1A.1,3,7

The following is the case of a 22-year-old woman with a rare primary presentation of RDD of bone: a solitary lesion in the proximal humerus with no clinical evidence of lymph node involvement.

Case presentation

A 22-year-old woman was referred to the oncological orthopedics department of a secondary care institution in Medellín (Colombia) due to pain in her right shoulder that had been present for two months without sustaining any prior trauma and refractory to oral analgesics and anti-inflammatory drugs, which had progressed to functional loss and muscle weakness in the limb. On physical examination, edema and tenderness were noted in the right shoulder, along with functional limitation and pain when raising the arm. No cervical or axillary lymphadenopathy or neurovascular deficit were observed. The QuickDASH score of the patient was 93.2, and she also reported high pain intensity (a score of 8-9 on the visual analog scale - VAS).

Initial X-rays and magnetic resonance imaging (MRI) scans, with and without contrast, of the right shoulder showed a 26 mm lytic lesion in the greater tuberosity of the humerus with well-defined isointense edges and surrounding bone edema extending to the proximal diaphysis, compromising the rotator cuff insertion points (supraspinatus tendon).

Figure 1. Initial shoulder X-rays. A. Anterior-posterior view. B. Lateral view. C. Zanca view.

Figure 2. Initial magnetic resonance imaging of the right shoulder. A. No contrast. B and C. With contrast.

Source: Images obtained while the patient was being treated.

Due to the size of the lesion and the presumptive diagnosis of chondroblastoma, seven days later, an excisional biopsy and oncological treatment of the right proximal humerus were undertaken. Furthermore, given the severity of the edema, prior to supraspinatus tendon avulsion and following rotator cuff repair, total synovectomy was performed with cortico-cancellous particulate allograft application to manage the residual defect. Since there were no perioperative complications, the patient was discharged the next day with instructions to attend a follow-up appointment.

The histopathological report of the surgical specimen, available 10 days after surgery, described the presence of abundant inflammatory infiltrate of lymphocytes, polymorphonuclear leukocytes (PMNs), histiocytes, and multinucleated giant cells in the fibrous connective tissue with no evidence of malignancy. Additionally, multiple large foamy macrophages were observed, some with emperipolesis. Immunohistochemical examination showed positivity for CD68 and S100 biomarkers in histiocytes, and negativity for DOG1, P63, CK, SATB2, LANGERIN, and CD1a proteins. It was not possible to evaluate the CD163 biomarker due to the decalcification process. Based on these findings, the patient was diagnosed with RDD (Figure 3).

Figure 3. Histopathological examination of the tumor lesion. A and B. Extensive emperipolesis (10x and 40x). C and D. Positivity in histiocytes for CD68 and S100.

Source: Images obtained while the patient was being treated.

Six weeks after surgery, a positron emission tomography (PET-CT) scan with fluorodeoxyglucose was performed to assess the extent of the disease, showing a slight increase in metabolism, of an inflammatory nature, in the periarticular soft tissues, skin, and subcutaneous tissue of the right shoulder. Moreover, bilateral cervical, axillary, and inguinal lymphadenopathy without adenomegaly was identified (Figure 4). On the other hand, follow-up X-rays showed adequate bone augmentation (Figure 5). The physical examination showed shoulder abduction and flexion up to 90°, a QuickDASH score of 34.1, and an EVA score of 5.

Figure 4. Positron emission tomography 6 weeks after surgery. A and B. Increased periarticular metabolism in the right shoulder. C. Bilateral cervical and inguinal lymphadenopathy.

Source: Images obtained while the patient was being treated.

Figure 5. X-ray of the right shoulder 6 weeks after surgery. A. Anterior-posterior view. B. Lateral view.

Source: Images obtained while the patient was being treated.

During a consultation with the hematology department specialist four months after the surgery, a bone marrow aspiration showed a reactive lymphoid cell population with normal CD19 and CD20 expression and negative CD5 coexpression. In addition, normal expression of CD3 and CD5 was observed in the T cell population, as well as an adequate proportion of gamma delta T cells and a preserved CD4/CD8 ratio. The results of the myelogram, flow cytometry, and bone marrow biopsy were normal. Based on these findings, it was decided that the best therapeutic approach for the patient was watchful waiting with periodic follow-ups.

At the follow-up appointment six months after surgery, a considerable improvement was observed in terms of pain (VAS score between 2-3), functionality (QuickDASH score of 4.5), and mobility of the right shoulder (abduction and flexion up to 120°, external rotation of 30°, and complete internal rotation without instability). Follow-up X-rays showed that the allograft had integrated properly, was in the correct position, and was in the process of consolidating; no new lesions or signs of tumor recurrence were identified (Figure 6).

Figure 6. X-rays of the right shoulder six months after surgery. A. Anterior-posterior view. B. Lateral view. C. Zanca view.

Source: Images obtained while the patient was being treated.

At a follow-up appointment 11 months after surgery, the patient reported progressive pain along with functional disability, so MRI scans of the right shoulder were performed, with and without contrast. The contrast-enhanced MRI showed a 16×15×10mm lytic lesion on the posterior and lateral aspects of the humeral head, possibly related to a recurrent tumor. No degeneration or tear of the rotator cuff tendons or joint effusion were observed (Figure 7).

Figure 7. MRI scans of the shoulder 11 months after surgery. A and B. No contrast. B. With contrast. A lytic lesion is observed in the humeral head.

Source: Images obtained while the patient was being treated.

Given these findings, 14 days later, the patient underwent a revision surgery with resection and curettage of the lesion for histopathological analysis, as well as local augmentation with autologous cancellous bone graft and cancellous bone graft chips. According to the histopathology report, there was no evidence of tumor recurrence, so it was concluded that the lesion was caused by bone graft resorption.

At the 30-month follow-up after the initial surgery and 18 months after the revision surgery, the patient showed adequate functionality and mobility in the right shoulder (full range of motion and QuickDASH score of 2.3) and reported a notable pain reduction (VAS score of 1). Moreover, X-rays of the right shoulder showed good bone healing without tumor recurrence (Figure 8). The patient remains under observation with follow-up appointments every six months.

Figure 8. X-rays of the right shoulder 18 months after revision surgery. A. Anterior-posterior view. B. Lateral view. C. Zanca view.

Source: Images obtained while the patient was being treated.

Discussion

In this article, we report the case of a young adult woman with a rare presentation of primary RDD of bone: a single lesion in the right proximal humerus with functional involvement of the shoulder and no obvious lymphadenopathy on physical examination. The tumor lesion was resected, and histopathological analysis reported the presence of pathognomonic features of emperipolesis and positivity for CD68 and S100 markers in histiocytes. The residual defect was corrected by augmentation with particulate cancellous bone graft and rotator cuff repair, achieving adequate functional recovery without tumor recurrence. However, one year after the procedure, the patient required a revision surgery due to bone graft resorption that compromised shoulder function. Recovery after this second procedure was also successful.

RDD is a rare histiocytic disorder first described in the 1960s as sinus histiocytosis with massive lymphadenopathy1,2,8 and subsequently classified as non-Langerhans cell histiocytosis in 1987.1 Currently, RDD is part of the “R group” of histiocytoses,1,4 which includes familial RDD, sporadic RDD, and other miscellaneous non-cutaneous, non-LC histiocytoses.1,3

The classic nodal form of the disease, which is a sporadic form of RDD, mainly affects children and young adults, with a slight predominance in males. Its clinical presentation involves massive bilateral cervical lymphadenopathy associated with fever, leukocytosis, weight loss, and night sweats.1-4

The extranodal form, which is another type of sporadic RDD, can be seen in over 40% of cases, with the majority presenting lymph node involvement.1,4 This form is mainly encountered in older patients, and sites of involvement include the skin, bones, head and neck (orbital and nasal cavities), central nervous system, glandular tissue, and kidneys and adrenal glands.1-5

Bone involvement due to RDD is rare (less than 10% of cases)2,6,9 and is more common in long bones such as the tibia, femur, and humerus, as well as the clavicle, craniofacial bones, and bones of the hands.6,7,9-11 Primary RDD of bone without clinically detectable lymph node involvement is extremely rare, accounting for approximately 1 to 2% of all cases,12 being described mainly in case reports or small series.6,7,9,11,13-18 This presentation poses a diagnostic challenge due to the nonspecific nature of the clinical manifestations, usually functional disability and pain at the affected site as the only symptoms due to inflammatory involvement of the soft tissue adjacent to the lesion.2,6,9,12,13,15,16,18,19

On X-rays, most lesions are lytic in appearance and centered in the medullary space with well-defined sclerotic margins, although they may also appear as sclerotic lesions with scattered lytic foci.5,6,9,11,20 In the case of MRI, the characteristic finding is edema of adjacent soft tissues, which is likely to be reactive, so this imaging technique is not very useful for ruling out differential diagnoses.5,6,9 Given the clinical and radiological characteristics, bone lesions can be mistaken for other conditions, including lymphoma, Langerhans cell histiocytosis, osteomyelitis, multiple myeloma, metastatic disease, sarcoma, aneurysmal bone cyst, plasmacytoma, chondromyxoid fibroma, enchondroma, and rare lipid storage diseases and sarcoidosis.7,9,13,14,16-18,20,21

RDD diagnosis is established histopathologically, as its tissue morphology has highly distinctive characteristics. Microscopic examination reveals a mixed inflammatory infiltrate consisting of large histiocytes, lymphocytes, and plasma cells. The pathognomonic finding is emperipolesis, defined as the presence of intact lymphocytes or plasma cells within the cytoplasm of histiocytes. Diagnostic confirmation is achieved through immunohistochemistry, with histiocytes positive for S100 and CD68 and negative for CD1a being the gold standard for detecting the disease.1,3,7

The characteristic histopathological findings of primary extranodal presentation in bones or primary RDD of bone are prominent lymphoid follicles with germinal centers, fibrosis, sclerosis, large nucleated histiocytes with hypochromatic nuclei, and subtle or unidentifiable emperipolesis.22 Similarly, in patients with extraganglionic involvement, diagnosis may be more difficult because bone and soft tissue lesions tend to have lower numbers of histiocytes and less obvious emperipolesis and often show areas of fibrosis or storiform spindle cell areas that resemble fibrohistiocytic lesions.2 In terms of immunohistochemistry, typical findings include positivity in histiocytes for S100 protein and for CD68 and CD163 biomarkers, as well as negativity for CD1a and CD207 Langerhans cell markers.2,4,5,9,11,13-15,19,22

The clinical and histopathological characteristics observed in our patient, atypical primary presentation of extraganglionic RDD (solitary lesion in the proximal humerus without clinically detectable lymph node involvement), are similar to those reported in several case reports of primary bone involvement due to RDD.7,9,13,14,18 Although chondroblastoma was initially suspected, histopathological analysis revealed the presence of emperipolesis (a phenomenon in which intact lymphocytes, neutrophils, plasma cells, or erythrocytes are phagocytosed) and biomarkers specific to the disease, which allowed us to establish the diagnosis.3,4 This demonstrates that the radiological diagnosis of primary RDD of bone is very difficult due to the variety of clinical manifestations and the relatively rare nature of the disease, and that, therefore, the diagnosis must always be confirmed by histopathology.3,4.

Regarding the therapeutic approach, it has been suggested that patients with multiple lesions have a better overall response to combination chemotherapy (with or without prednisone) than to single-agent schemes.1,2 However, in individuals with a single lesion, such as our patient, tumor resection is recommended, as well as an assessment by the hematology/oncology service.1,2 It should be noted that in our case, the hematology/oncology service concluded that the best therapeutic option for the patient was to attend regular follow-up appointments rather than begin systemic therapy.

In general, RDD has a good prognosis with spontaneous regression of lesions.1,9 In our patient, lesion resection yielded satisfactory clinical and functional outcomes, with no evidence of recurrence at the last follow-up appointment at the time of writing this case report. However, it is worth mentioning that 11 months after surgery, bone graft resorption was interpreted radiologically as recurrence, leading to a revision surgery. Following the second intervention, shoulder function and pain continued to improve, and at the last follow-up, the patient showed adequate functionality and mobility of the affected shoulder and reported that the pain was almost imperceptible.

Conclusion

This case describes the clinical, imaging, and histological characteristics of a rare presentation of primary RDD of bone (solitary lesion in the proximal humerus). This condition should be suspected in the presence of an atypical lytic bone lesion, particularly in young people. Given its very rare occurrence and the wide variety of differential diagnoses, diagnosing it is challenging, so it is very important to be familiar with its main clinical, radiological, and histopathological characteristics. Furthermore, as demonstrated in this case, timely diagnosis and appropriate treatment for this condition requires a multidisciplinary approach involving specialists in radiology, orthopedic oncology, pathology, and hematology/oncology.

Ethical considerations

For the preparation of this case report, informed consent was obtained from the patient, who authorized the use of her medical history, imaging tests, and other diagnostic studies for this purpose. Approval was also obtained from the ethics committee of the hospital where she was treated.

Conflicts of interest

None stated by the authors.

Funding

None stated by the authors.

Acknowledgements

None stated by the authors.

References

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