An Overlap of Erdheim–Chester Disease and Rosai–Dorfman Disease With Isolated Bone Lesions Presenting a Diagnostic Challenge: A Case Report

ABSTRACT

Some of the rarest diseases with cell accumulation in different organs are histiocytoses. Since these diagnoses are uncommon, other differential diagnoses must be excluded. We report a case of a 42‐year‐old man with episodes of knee pain and fever. Multiple sclerotic bone lesions were discovered by ¹⁸F‐fluorodeoxyglucose positron emission tomography‐computed tomography (FDG PET/CT). A bone biopsy was taken, and it showed a mixed infiltrate consisting of mature lymphocytes, plasma cells, and many histiocytes (CD68 ⁺ /CD163 ⁺ /S‐100 ^−/+ /CD1a ⁻ /langerin ⁻ ), including some foamy macrophages and cells with emperipolesis. Histology showed characteristics for both Erdheim–Chester disease (ECD) and Rosai–Dorfman disease (RDD). Molecular analysis showed MAP2K1 mutation that can be seen with both diseases. Considering the clinical manifestations that resembled ECD and histologic RDD‐like features, a diagnosis of overlap between ECD and RDD with isolated multifocal bone involvement was made. Treatment with pegylated interferon alfa (Peg‐IFN‐α) was started, and after three months clear clinical improvement was reported by the patient, although PET/CT demonstrated metabolically stable disease.

Key Clinical Message

Histiocytoses may present with overlapping features and therefore complicate diagnosis and management, which may lead to delays in starting the correct treatment. Clinicopathological correlation is important to achieve an accurate diagnosis and correct treatment.

1. Introduction

Histiocytoses are a heterogeneous group of uncommon disorders that can mimic many other diseases, including malignant tumors, since the hallmark of the disease is accumulation and infiltration of pathological histiocytes in tissues. Clinical features are highly variable depending on anatomical sites involved and can vary from mild single‐organ involvement to systemic life‐threatening disease. Current consensus recommendation classifies histiocytosis into five groups, which is based on involved cells (derived from macrophages, monocytes, or dendritic cells), clinical and imaging findings, phenotype and molecular alterations. Many histiocytoses are known as clonal neoplastic diseases driven by different somatic mutations. Although there are over 100 subtypes of histiocytoses, this case report focuses only on those subtypes that were relevant differential diagnosis options, which were: juvenile xanthogranuloma (JXA), ECD, RDD, ALK‐positive histiocytosis (APH), Langerhans cells histiocytosis (LCH), and histiocytic sarcoma (HS) (summarized in Table 1) [1, 2]. During the last decade overlapping histiocytosis variants have been described—ECD with LCH and ECD with RDD. The latter is more infrequent. ECD‐RDD overlap is described in cases where histology is characteristic of RDD, but clinical findings resemble more ECD [3, 4].

TABLE 1.

Overview of histiocytic neoplasms, Langerhans and non‐Langerhans neoplasms that can have bone lesions [1, 2].

	The median age at diagnosis	Most common involvement sites	Clinical symptoms	Cell morphology	Typical mutations
JXG/AXG	0–12 months; can also occur later in life	Typical is skin involvement. Extracutaneous lesions can be seen in eye region, lungs, soft tissues, spleen, CNS, and rarerly in bones.	Solitary yellowish‐red cutaneous nodules (usually spares the epidermis).	Foamy cells or xanthomatized histiocytes, Touton cells and foreign‐Body giant cells. Macrophages, lymphocytes.	MAP2K1, KRAS/NRAS Seldom: CSF1R mutation or NTRK1fusion
ECD	Peak: 55– 60 years	Bones (> 95%), lungs, skin, retroperitoneal space, CNS, cardiovascularsystem (50%), orbital involvement.	Main symptom is bone pain, caused by bilateral symmertrical osteoslerosis of the long bones.	Foamy mono/multinucleated histiocytes, Touton giant cells. Lymphocytes, plasma cells, neutrophils.	Most common BRAF V600E mutation. Seldom: MAP2K1
Extranodal RDD	~40 years	Skin, sinuses, bones (isolated lytic lesions), soft tissue, retro‐orbital tissue, lymph nodes, and CNS.	Painless lymphadenopathy, but also systemic symptoms (fever, fatigue, weight loss).	Histiocytes with vesicular nuclei, emperiopolesis.	KRAS, MAP2K1
APH multisystemic disease variant	~7 years; can also occur later in life	Lungs, bones, liver, lymph nodes, CNS, and skin.	Cough, bone pain, hepatomegaly, lymphadenopathy, headaches, cutaneous lesions.	Large histiocytes with small nucleoli. Foamy histiocytes, Touton giant cells and empeiopolesis.	Most common KIF5B–ALK fusion
LCH	~3 years; can also occur later in life	Bones, skin, pituitary gland, liver, spleen, lungs, lymph nodes, and CNS.	Bone pain, persistent rash, diabetes insipidus, lymphadenopathy, tissue swelling.	Mononucleated cells with a large, grooved nucleus (coffee‐bean shaped).	BRAF V600E, MAP2K1
HS	Peak: 50–69 years; rare in children	Lymph nodes, skin, gastrointestinal tract, bones (rare), soft tissue, spleen, and liver.	Lymphadenopaty, bone pain, hepatosplenomegaly. Systemic symptoms: fever, fatigue, sweating, weight loss.	Large pleomorphic cells with oval/irregular nuclei. Multinucleation can be seen. Hemophagocytosis and tumor cells.	BRAF, KRAS, MAP2K1

Abbreviations: APH, ALK‐positive histiocytosis; AXG, adult xanthogranuloma; CNS, central nervous system; ECD, Erdheim–Chester disease; HS, histiocytic sarcoma; JXG, juvenile xanthogranuloma; LCH, Langerhans cells histiocytosis; RDD, Rosai–Dorfman disease.

RDD is an idiopathic histiocytosis that is often self‐limited in classical form. It was first reported in 1969 by Rosai and Dorfman and nowadays is classified separately in R‐group according to histiocytosis classification [1]. RDD affects most frequently young adults and is slightly more common among males. Classical clinical findings include enlarged painless cervical lymph nodes and unspecific systemic symptoms (fever, weight loss, etc.). Extranodal symptoms are less frequent, but skin, bone, sinonasal, soft tissue, and other sites infiltration have been reported [5, 6].

ECD is a rare subtype of non‐LCH, where accumulation of foamy histiocytes with small nuclei and some multinucleated histiocytes can be seen. It is estimated that fewer than 1000 cases occur worldwide each year. ECD can be seen more often among middle‐aged males. One of the most typical findings (> 95%) with ECD is bone lesions that present bilaterally in the long bones. But lesions can also involve the central nervous system, retroperitoneal space, perinephric tissue, cardiovascular system, skin, etc. [1, 7, 8]. Therefore, histologic differentiation is essential. RDD has characteristic histiocytic infiltrate with CD68⁺ S‐100⁺ CD1a⁻ histiocytes and strong emperipolesis [5]. On the other hand, the histology of ECD is not specific—histiocytes are typically foamy, some Touton cells can be observed, and to some extent emperipolesis can be observed. Histiocytes can be positive for CD68 and some for S100 protein. Mutations are typically found in the MAP‐kinase signaling pathway [7, 8]. The most frequent gain‐of‐function mutation is BRAF V600E in patients with ECD [9]. Patients with ECD and RDD overlapping forms often have MAP2K1 mutations [4].

We present a case of overlapping ECD and RDD with isolated bone lesions to emphasize the need for careful evaluation and correlation of clinical findings and histology, including the significance of immunohistochemistry staining, to make a correct diagnosis.

2. Case History/Examination

A 42‐year‐old man was referred to an internist after 12 months of episodic right knee pain and fever over 38°C. He reported that the symptoms occurred only during the nighttime. He reported no history of trauma or prior joint disorders. At first, the episodes occurred once a month, but over time their frequency increased to every other night. On physical examination, there were no abnormalities, no restriction of motion, or swelling of the joints. The patient reported a weight loss of 10 kg over the last year. His medical history included arterial hypertension and the only medication he regularly used was telmisartan 40 mg per day.

3. Differential Diagnosis, Investigations and Treatment

Laboratory test showed mild leukocytosis and mildly elevated C‐reactive protein (CRP) 14 mg/L (normal range < 5 mg/L). Other laboratory investigations showed no evidence of infection, autoimmune disease, or underlying hematological disorder.

The first imaging examination was a knee X‐ray, which revealed no findings explaining the patient's symptoms. As there was no joint swelling, ultrasound of the joint was not considered indicated. Given the presence of systemic symptoms and rising suspicion of malignancy, a whole‐body CT scan was performed. It showed unrelated mild chronic sinusitis in the left maxillary sinus and some lymph nodes bilaterally in the carotid sheath, which were all less than 1 cm in diameter.

Since all the imaging findings were unspecific, a PET/CT was done, and it showed FDG accumulation involving approximately 15 skeletal lesions (Figure 1), of which the biggest infiltrations were seen in the manubrium of the sternum, in the left acetabulum, and bilaterally in the femur and tibia. SUVmax of the largest skeletal lesion, located in the right medial femoral condyle, was 15.7. To make a definitive diagnosis, a bone core needle biopsy was taken from the right tibial bone. Histology showed fibrotic stroma in between bone trabeculae, accompanied by a prominent lymphohistiocytic infiltration, including many mainly small histiocytic cells. Many plasma cells were immunoglobulin G4 (IgG4)‐positive: up to 100 cells per high‐power field (HPF), and the IgG4:IgG ratio was slightly over 40%. Proliferative activity was very low, and there were no malignant cells, so malignancy was excluded. Subsequently, blood IgG4 level was measured for the first time and found to be elevated to 2.04 g/L. To exclude hematological malignancy, a bone marrow biopsy was performed, which showed only reactive changes. The diagnosis was inconclusive at this point. A rheumatologist was consulted, and the patient was hospitalized to the rheumatology department. The clinical presentation remained unchanged. Based on bone lesions, elevated IgG4 levels, and IgG4‐positive (IgG4+) cells in the bone biopsy, a preliminary diagnosis of IgG4‐related disease (IgG4‐RD) was made, and treatment with prednisolone at a dose of 60 mg daily was started. Shortly after, rituximab 1000 mg was added because the disease was so profound. Before the initial treatment, CRP was 14 mg/L, and one month later the level dropped to 2 mg/L. After four months, the patient stopped responding to treatment when the prednisolone dosage was lowered below 15 mg.

FIGURE 1.

(1A) Coronal CT image demonstrates a sclerotic lesion involving the manubrium of sternum (yellow arrow). (1B) Corresponding axial FDG PET‐CT image reveals increased metabolic activity at the same site (white arrow). In addition, there is increased FDG uptake in the vertebral arch at the level of Th5 vertebra (black arrow). No corresponding lesion could be identified on CT imaging. (2A) Coronal CT image demonstrates an ill‐defined sclerotic lesion in the left acetabulum (yellow arrow). (2B) Corresponding axial FDG PET‐CT image reveals increased metabolic activity in the same region (white arrow). (3A) Coronal CT image demonstrates large sclerotic lesions involving the lateral and medial condyles of the right femur as well as the medial condyle of the right tibia (yellow arrows). (3B) FDG PET‐CT shows hypermetabolic lesions in the condyles of the right femur (white arrows). (3C) FDG PET‐CT demonstrates increased FDG uptake in a lesion located in the medial condyle of the right tibia (black arrow). (4) FDG‐PET‐CT image. Maximum intensity projection PET‐CT image demonstrates numerous FDG‐avid lesions involving the right clavicle, distal left humerus, sternum, left acetabulum, bilaterally femur and tibia and both feet.

The IgG4‐RD diagnosis was reevaluated, since the patient did not have classical clinical findings of IgG4‐RD and there was no storiform fibrosis, nor obliterative phlebitis seen in histology. It showed lymphohistiocytic cells and some foamy macrophages, indicating a histiocytosis. Many histiocytosis subtypes can involve bones: JXG, ECD, RDD, APH, LCH, and HS (as shown in Table 1), which made it difficult to establish the correct diagnosis at first. Therefore, histology evaluation was essential, but our laboratory could not determine the subtype, and the histology sample was referred to an external laboratory for further evaluation.

The immunohistochemistry showed S100 expression in atypical cell collections, variable emperipolesis, and CyclinD1 overexpression (Figure 2). In some histiocytes, CD68 and CD163 were positive. Overall, based on sent bone samples, it was concluded that morphology and immunophenotype were in accordance with non‐Langerhans cell histiocytosis in the Erdheim–Chester disease spectrum.

FIGURE 2.

Histopathology of right medial femoral condyle. (A) Hematoxylin–eosin‐stained section shows histiocytic infiltrate. (B) Immunohistochemistry shows S100 positive staining in histiocytes. Emperipolesis—lymphocytes (blue cells) can be seen inside histiocytes (brown cells) (H&E 400×).

Owing to the delay in obtaining the results, a new evaluation was performed four months later. The patient's symptoms had worsened: the pain was more frequent and started occurring during daytime. Also, laboratory findings showed a mild inflammatory response, CRP was 37 mg/L. A follow‐up PET/CT scan was performed to evaluate disease progression: It showed the same osteosclerotic type lesions with mildly diminished metabolic activity. There were no new lesions, and lymph nodes were small and metabolically inactive. It was concluded that rituximab was ineffective. Since non‐LCH is a hematologic malignancy, a hematologist was consulted, who decided that molecular analysis is needed to confirm the diagnosis. So, a new biopsy was taken from the right medial femoral condyle. Histology showed the same kind of histiocytes as were described before. The difference was in the proportion of cells—in the new biopsy histiocytic infiltrate dominated and there were fewer lymphocytes and plasma cells, including fewer IgG4+ plasma cells (up to 20 cells per HPF and IgG4:IgG ratio 10%–20%). The decrease in IgG4+ plasma cells was an expected effect from the rituximab treatment. Also, DNA analysis, next‐generation sequencing (NGS) was done, and it showed MAP2K1 mutation—this mutation can be evident for both diseases ECD and RDD [4, 5]. To confirm that the disease is confined to the skeletal system, magnetic resonance imaging of the heart and brain was performed and demonstrated no pathological lesions.

4. Conclusion and Results (Outcome and Follow‐Up)

The patient was referred to a hematologist who started treatment with Peg‐IFN‐α 90 mcg per week because MEK inhibitors were not available in our country at that time. At the same time, prednisolone was tapered down. After 3 months of treatment, the patient did not report pain or fever. A new PET/CT showed stable lesions. The patient continued the same treatment and symptoms monitoring after every three months.

5. Discussion

Histocytoses are uncommon infiltrative disorders that are characterized by accumulation of dendritic cells, macrophages, and/or monocyte‐derived cells. Since histiocytosis is not limited to one tissue or organ, it can mimic many other diseases. The only definitive way to distinguish it from other diseases is to take a biopsy and, based on symptoms, histology, and molecular analysis in correlation with clinical findings, make the diagnosis [1]. This case was relatively challenging. The first hypothesis based on clinical symptoms was chronic nonbacterial osteomyelitis (CNO) because joint pain was the main symptom, although no swelling was evident. However, this diagnosis was excluded by histology, which showed, in addition to inflammatory cells, also pathologic histiocytes with specific morphologic and immunophenotypic features [10]. Based on the first histopathology, it was assumed that IgG4‐RD would be the likeliest diagnosis. There were IgG4 positive plasma cells in the first specimen (IgG4:IgG ratio > 40%) and elevated IgG4 levels in the blood analysis. Although symmetrical lesions in the long bones have not been described with IgG4‐RD. The 2019 American College of Rheumatology/European League against Rheumatism classification criteria for IgG4‐RD were used—the exclusion criteria mentioned long bone abnormalities that are consistent with ECD [11]. Accordingly, disease history was reevaluated in this light, and histology was sent to an external laboratory where non‐LCH was diagnosed.

In 2016 a new classification of histiocytoses was published, where ECD and RDD were distributed to different subgroups [1]. But lately some case reports have been published based on clinical, histopathological and imaging findings showing that histiocytoses may overlap [3, 4]. The presented case showed characteristics of both diseases, making the diagnosis and treatment selection more challenging.

Firstly, ECD is more common among 55‐ to 60‐year‐old male patients and RDD is more common among younger adults [1]. Skeletal involvement is seen more with ECD, and bone pain is most frequently the first symptom, whereas patients with RDD report more constitutional symptoms and lymphadenopathy [5, 7]. Our patient was in their early 40's when knee pain and fever first appeared, but he never developed lymphadenopathy. Although extra nodal involvement is seen in up to 40% of all RDD cases, bone lesions are not that common and isolated bone lesions are seen in less than 8% of all RDD cases [5, 12, 13]. ECD bone lesions are described as bilateral symmetric cortical sclerotic lesions and are best visualized on the PET/CT or technetium‐99 bone scan [7]. In both diseases, femoral and tibial infiltration have been described. Facial bone lesions could also be seen in both cases, but slightly more with ECD [5, 7]. Based on clinical and radiological findings, it was deduced at first that this patient can be diagnosed with ECD. To confirm the diagnosis, multiple biopsies and genetic testing were done. The histology showed characteristic findings of RDD—large histiocytes that showed S100 expression and a variable degree of focal emperipolesis that was associated with overexpression of cyclin D1 in the nuclei. Also, IgG4+ cells have been described in patients with RDD diagnosis, and it is recommended to measure IgG4+ cells ratio [1]. There were some characteristics that are typical of ECD—foamy histiocytes (CD68⁺/S‐100^−/+/CD1a⁻/langerin⁻) and giant macrophages. Emperipolesis is rare in ECD [8].

Since the first biopsy had poor DNA quality, a new biopsy was taken from the right femoral bone. Molecular analysis showed MAP2KI mutation, more precisely mitogen‐activated protein kinase pathway involvement, that is in compliance with cyclin D1 overexpression. The patient did not have BRAFV600E mutation, which is estimated to be found in around 50% of patients with ECD [7, 9]. There are some reports where BRAFV600E mutation has been detected in patients with RDD, but it is uncommon [9]. Based on these findings, it was proposed that the diagnosis is an overlap between ECD and RDD. The clinical findings were characteristic of ECD, but histology findings were more consistent with RDD. The first report of this kind of overlap was proposed by Razanamahery et al. in 2020 [4]. Later, other authors have reported the same kind of overlap variant, and one common variable is that most of the patients have MAP2K1 mutations, which seems to be the common driver mutation [3, 4, 14]. Patients with overlap of these two diseases have also reported testicular infiltration, but our patient did not have infiltration in any other place than bones [4].

Based on the MAP2K1 mutation, the first treatment choice should have been MEK‐inhibitors. Historically, interferon‐α, including pegylated formulations, has been used to treat ECD and it has shown good results; therefore, it is still recommended treatment, even though it has many side effects [8]. With RDD, recommended treatment options are steroids, chemotherapy, radiotherapy, and immunomodulatory agents [5]. Our patient started taking glucocorticoids since the suspicion of IgG4‐RD emerged, which did have some effect clinically in high doses, but it had no effect on the lesions. Then, rituximab therapy was initiated and four months later, the PET/CT scan showed minimal changes in the metabolic activity, but disease episodes remained. Since our patient had clinical findings that were most characteristic of ECD, and we did not have access to MEK‐inhibitors, the treatment with Peg‐IFN‐α was the next choice. After three months, the outcome was satisfactory—clinical symptoms decreased and the PET/CT scan showed stable lesions. Some case reports and reviews have suggested that radiological responses may lag even in the presence of good clinical improvement [14].

In conclusion, this case represents an unusual non‐Langerhans histiocytosis entity with isolated polyostotic lesions, which are rare manifestations in non‐Langerhans histiocytosis. We considered this case to be an overlap of ECD and RDD with mixed histological findings slightly more characteristic of RDD because of emperipolesis. Shared features between ECD and RDD have been increasingly recognized in case reports; therefore, a multidisciplinary diagnostic approach is needed to understand the spectrum of histiocytic diseases.

Author Contributions

Maris Tulk: conceptualization, investigation, resources, visualization, writing – original draft, writing – review and editing. Reet Kuuse: conceptualization, investigation, supervision, writing – review and editing. Maksim Zagura: visualization, writing – review and editing. Hazem M. M. Ali: investigation, supervision, writing – review and editing. Liis Vahesaar: investigation, visualization, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

Ethical approval was not required for this case report, as the report describes a single patient and written informed consent was obtained.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal if requested.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The relevant clinical, radiological, and pathological data supporting the findings of this case report are included within the article.