Rosai-Dorfman disease: A rare presentation as an isolated axillary lymphadenopathy, a case report and literature review

Abstract

Introduction

Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm. It most commonly presents with bilateral cervical lymphadenopathy. We report the fourth case in the literature of RDD presenting as isolated axillary lymphadenopathy.

Case report

We report the case of a 55-year-old female patient who presented with right axillary lymphadenopathy that had persisted for 1 year, without other associated symptoms. Physical examination revealed an isolated right axillary lymphadenopathy. An excisional biopsy of the lymph node was performed, and histopathological findings were consistent with Rosai-Dorfman's disease. Regular follow-up was recommended.

Discussion

RDD is an uncommon histiocytic disorder. Initially identified in the 1960s as a benign, self-limited condition, RDD is now classified as a neoplastic disorder with causative mutations in the MAPK pathway. The classic presentation involves extensive, painless bilateral cervical lymphadenopathy. Isolated axillary lymph node involvement, as seen in our patient, is a rare presentation of nodal RDD with only three cases reported in the literature to date. Histologically, RDD is characterized by a prominent histiocytic infiltrate set against a background of inflammatory cells, primarily composed of lymphocytes and plasma cells. These histiocytes are typically hypochromatic, with abundant pale cytoplasm, and exhibit varying degrees of emperipolesis. In 2018, consensus guidelines for the management and evaluation of RDD were introduced.

Conclusion

Recent advances in genetic sequencing have reclassified RDD from a benign inflammatory disorder to a histiocytic neoplasm. Further research is needed to fully understand its implications for prognosis and treatment strategies.

Highlights

• •Rosai-Dorfman disease is a rare histiocytic neoplasm.
• •It most commonly presents with bilateral cervical lymphadenopathy.
• •Isolated axillary lymph node involvement is a rare presentation of nodal Rosai-Dorfman Disease with only three cases reported in the literature to date.
• •We report the fourth case in the literature of Rosai-Dorfman Disease presenting as an isolated axillary lymphadenopathy.

1. Introduction

Rosai-Dorfman disease (RDD) is an uncommon histiocytic disorder [1]. It was first identified in the 1960s as a benign, self-limited condition characterized by widespread lymphadenopathy. In the 1990s, a larger cohort of 423 patients with predominantly extranodal involvement was reported [2]. Since then, significant advancements have been made in understanding its genetic factors, particularly the MAPK pathway [3,4]. RDD is now classified as a neoplastic disorder by the World Health Organization's classification of hematopoietic malignancies [5]. RDD typically presents with bilateral cervical lymphadenopathy [6]. Extranodal and cutaneous forms are recognized. The clinical course of RDD varies widely, ranging from a self-limited condition to disseminated, refractory disease with increased mortality. Due to the heterogeneity of the disease, treatment strategies for RDD differ and may involve either localized or systemic approaches [7]. Isolated axillary lymph node involvement is a rare presentation of nodal RDD with only three cases reported in the literature to date. In this report, we describe the fourth case of RDD manifesting as an isolated axillary lymphadenopathy. This case report is reported according to the SCARE criteria [8].

2. Case report

We report the case of a 55-year-old female patient who had no medical history, did not smoke, and had no history of alcohol consumption or drug use. She had no notable family history, particularly of malignant hematologic diseases or Rosai-Dorfman disease. She presented with a persistent right axillary lymphadenopathy for one year, without associated fever, night sweats, weight loss, or anorexia. Upon questioning, there was no history of tuberculosis exposure, consumption of unpasteurized dairy products, high-risk behavior for sexually transmitted infections, or any history of cat scratches, contact with cats or their litter, or proximity to animals in her environment. Upon examination, there was a 5 cm mobile right axillary lymphadenopathy with a firm consistency, without any local inflammatory signs, and no other palpable lymph nodes. The breast examination was unremarkable, and the rest of the physical exam was normal. The biological workup was unremarkable, with a normal complete blood count and C-reactive protein levels. The Tuberculin skin test was negative and the chest X-ray showed no abnormalities. Breast ultrasound and mammography were performed, and no abnormalities were observed. However, axillary ultrasound revealed a 5 cm right axillary lymphadenopathy with an indeterminate appearance, requiring histological confirmation. The patient underwent an excisional biopsy of the right axillary lymphadenopathy. The histopathological examination revealed a lymph node parenchyma with significant distension of the interfollicular spaces, characterized by an accumulation of macrophages, lymphocytes, plasma cells, and a few neutrophils (Fig. 1). These macrophages were enlarged, with abundant, clear, or sometimes foamy cytoplasm, and showed emperipolesis of lymphocytes (Fig. 2). Immunohistochemical analysis demonstrated diffuse expression of the S100 protein by the macrophages (Fig. 3). They were negative for CD1a (Fig. 4). These morphological and immunohistochemical findings were consistent with Rosai-Dorfman disease. The case was presented at a multidisciplinary team meeting, where it was concluded that treatment was complete since the lymphadenopathy had been entirely resected. Regular follow-up was recommended. Currently, at 18 months of follow-up, the patient remains in full remission.

Fig. 1.

A prominent histiocytic infiltrate within a background of inflammatory cells, predominantly consisting of lymphocytes and plasma cells.

Fig. 2.

Lesional macrophages characterized by an enlarged size, abundant clear or occasionally foamy cytoplasm, and showing emperipolesis (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3.

Macrophages with emperipolesis immunoreactive for S100 (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4.

Macrophages non-immunoreactive for CD1a.

3. Discussion

With an incidence of 1:200,000, RDD is a relatively uncommon condition, with only 100 new cases reported each year in the United States [3]. RDD typically affects young adults with a minor male predominance [7]. The male-to-female ratio is 3:2, and the mean age upon diagnosis for RDD is roughly 20.6 years [7].

The most common form is sporadic RDD, which includes the classic nodal type, extranodal RDD, neoplasia-associated RDD, and immune disease-associated RDD [9]. Erdheim-Chester disease, leukemias, malignant histiocytoses, Langerhans cell histiocytosis, and lymphomas are among the neoplasms associated with RDD [1]. Moreover, autoimmune hemolytic anemia, systemic lupus erythematosus, idiopathic juvenile arthritis, and HIV are immune diseases linked to RDD [1]. H syndrome, also known as Faisalabad syndrome, is an uncommon autosomal recessive genetic disorder that is linked to familial RDD [1]. In the case of our patient, the disease was isolated, and no family history of RDD was reported. The diagnosis of sporadic RDD in its classic nodal form was made.

RDD aetiopathogenesis is not well known. It was previously considered a benign inflammatory disorder with an unknown origin. However, recent molecular studies have identified recurrent somatic gain-of-function mutations in MAPK pathway genes in a subset of RDD cases, supporting the notion of a clonal histiocytic proliferative process. As a result, RDD is now classified as a neoplastic myeloproliferative condition [2,3]. Kinase mutations in ARAF, MAP2K1, NRAS, and KRAS are present in nodal and extranodal RDD according to recent investigations [10,11]. RDD has also been studied for BRAF V600E mutations, which have been connected to histiocytic neoplasms such as Erdheim Chaster disease [12].

The classic presentation of RDD includes extensive bilateral painless cervical lymphadenopathy with concomitant fever, loss of weight, and night sweats [13]. There may also be involvement of the mediastinal, retroperitoneal, and inguinal lymph nodes [9]. Extranodal presentation occurs in more than 40 % of cases, with the skin, nasal cavity, bone, orbital tissue, and nervous system being the more common extranodal sites of involvement [3]. An isolated axillary lymph node involvement, as observed in our patient, is a scarce presentation of nodal RDD. To our knowledge, only three cases have been reported in the literature (Table 1).

Table 1.

Reported cases of Rosai-Dorfman disease presenting with an isolated axillary lymphadenopathy.

Case	Author year	Age	Sexe	Location	Size	Specimen type	Histology	IHC	Treatment	Reference
1	Shetty et al. 2020	33	F	Left axillary lymphadenopathy	3.5 cm	Lymph node excision	Histiocytic infiltrate + emperipolesis	S100(+) CD31(+) CD68(+) Cd1a(−) CD3(−) CD20(−)	Lymph node excision	[14]
2	Shetty et al. 2020	88	F	Right axillary lymphadenopathy	2.7 cm	Lymph node excision	Histiocytic infiltrate + emperipolesis	S100(+) CD138(+) CD79a(+) CD3(−) CD20(−) kappa(−) lambda(−) PAX5(−) MUM1(+)	Lymph node excision	[14]
3	Banga et al. 2022	23	F	Right axillary lymphadenopathy	1.5 cm	Fine needle aspiration cytology	Histiocytic infiltrate with lymphocytes and plasma cells + emperipolesis	ND	Follow-up without any intervention	[15]
Present case	2023	55	F	Right axillary lymphadenopathy	5 cm	Lymph node excision	Histiocytic infiltrate with lymphocytes and plasma cells + emperipolesis	S100(+) CD68(+) CD3(+) CD20(+) CD23(+) CD1a(−)	Lymph node excision

ND: no data.

The most significant histological finding in RDD is an enlarged lymph node with broad sinusoidal expansion [16]. The cortex is composed of numerous mature plasma cells, with sparse follicles and abundant activated B cells. The sinusoids are filled with numerous large histiocytic cells characterized by smooth-contoured hypochromatic nuclei, small centrally located nucleoli, and poorly defined pale cytoplasm [9,16]. A useful but non-specific feature is emperipolesis, where intact hematolymphoid cells appear freely within the cytoplasm of histiocytes or enclosed in vacuoles [3]. The histiocytes are positive for S100, CD68, and CD163, but negative for CD1a and langerin (CD207) which excludes Langerhans cell histiocytosis (LCH). The S100 stain often highlights the emperipolesis [1]. In the four cases previously reported, including our patient's case, histological examination revealed an infiltrate of large histiocytes with abundant clear cytoplasm. Emperipolesis was also observed in all cases. In three cases where immunohistochemistry was performed, S100 was positive, while CD68 was positive and CD1a was negative in two cases.

The most important differential diagnosis for RDD is LCH. Nodal RDD can also mimic conditions such as anaplastic large-cell lymphoma, metastatic carcinoma, malignant melanoma, sinus histiocytosis, and other disorders with prominent sinusoidal patterns. These can typically be distinguished through immunohistochemistry [1].

In 2018, consensus guidelines for the management and evaluation of RDD were published [3]. Patients with asymptomatic cutaneous involvement or simple lymphadenopathy should be followed up without intervention. In cases involving symptomatic airway, cranial, spinal, or sinus disease, as well as unifocal extranodal disease, surgical excision may be required. Currently, there is no standardized protocol for systemic therapy, which may be needed for patients with multifocal, unresectable extranodal disease. Systemic treatment options include corticosteroids, sirolimus, radiation, chemotherapy, and immunomodulatory therapy [3]. Corticosteroids have been utilized in the treatment of RDD due to their ability to reduce nodal size and alleviate symptoms. External beam radiation therapy is an option for patients with localized, unresectable, symptomatic masses that are refractory to steroid treatment, particularly in extranodal sites. Chemotherapy and immunotherapy have also been employed to manage RDD, with various chemotherapeutic agents yielding mixed treatment outcomes and potential adverse effects [7,17,18]. Of the three cases reported previously, two involved excisional biopsy of the lymphadenopathy, similar to our patient's case. In the third case, where the diagnosis was confirmed through fine-needle aspiration, regular follow-up was advised. This case showed a gradual reduction in the size of the lymphadenopathy, with complete resolution after 3 months [14,15].

Nodal RDD generally has a favorable prognosis. Spontaneous remission has been reported in up to 50 % of sporadic RDD cases [19]. However, up to 10 % of patients may die from the disease due to complications, infections, or amyloidosis [19].

4. Conclusion

We aim for this article to remind practitioners to include RDD in the differential diagnosis of isolated axillary lymphadenopathy and that thorough histological examination can facilitate an accurate diagnosis and guide appropriate management. Further investigation is needed to fully characterize the range of molecular alterations in RDD. The impact of these findings on prognosis and treatment is yet to be clarified.

Author contribution

Eya Rahmouni: writing

Racha Ben Romdhane: writing

Sabrine Boukhris: assisted in the writing of the manuscript and corrections

Houyem Mansouri: assisted in the writing of the manuscript and corrections

Houda Henchiri: assisted in the writing of the manuscript and corrections

Leila Achouri: read and approved the final version of the manuscript

Consent

Written informed consent was obtained from the patient for publication of the details of this medical case and any accompanying images.

Ethical approval

Ethical approval for this study (Ethical Committee number 24/073) was provided by The Ethical Committee Research Ethics Committee of the Regional Hospital of Jendouba, Jendouba, Tunisia on August 19, 2024.

Guarantor

Eya Rahmouni.

Funding

No funding or sponsors.

Declaration of competing interest

All authors declare no conflicts of interest.