Extranodal Rosai-Dorfman disease with bilateral renal involvement: A diagnostic challenge

Abstract

Rosai–Dorfman disease (RDD) is a rare, benign, non-Langerhans cell histiocytosis disorder. Extranodal involvement is present in a significant number of cases; however, renal manifestations are infrequent, often resembling malignant conditions, leading to a diagnostic challenge. We present the case of a 51-year-old male with a six-month history of fatigue, generalized weakness, and cervical lymphadenopathy. Computed tomography (CT) revealed multiple pulmonary nodules, mild hepatomegaly, and bilateral renal masses encasing the renal vessels and proximal ureters. Positron emission tomography–computed tomography (PET-CT) showed metabolically active renal lesions along with hypermetabolic cervical and abdominal lymphadenopathy, which were initially suggestive of lymphoma. On renal biopsy, sheets of large histiocytes displaying emperipolesis, with immunohistochemical positivity for S100 and CD68, were found, thereby confirming RDD. This case highlights the significance of considering RDD in the differential diagnosis of bilateral renal masses accompanied by systemic lymphadenopathy. The definitive diagnosis depends on histopathological analysis, and prompt systemic therapy can lead to stabilization of the disease.

Introduction

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare disease. It is a non-Langerhans cell histiocytic characterized by the proliferation of distinctive histiocytes within lymph nodes and extranodal tissues [1]. RDD generally manifests with the involvement of lymph nodes; however, extranodal sites are also involved in about 40% cases. The extranodal RDD can occur with or without lymphadenopathy and can affect a wide range of anatomical sites, including the skin, orbit, respiratory tract, bones, central nervous system, and kidneys [2]. Renal involvement in RDD is very rare, occurring in <5% of cases. It can mimic malignancy, especially lymphoma or metastatic disease, on radiological imaging, often requiring histopathological analysis and immunohistochemistry. RDD remains a diagnostic challenge attributed to its rarity and varying presentation [3]. We presented this case of RDD with bilateral renal involvement and multiple systemic lesions.

Case presentation

A 51-year-old male presented with the complaint of fatigue and weakness for the last 6 months without any other associated symptoms. He had no significant past medical or family history. The patient had no history of any addiction or drug intake. On examination, the patient had bilaterally enlarged cervical lymph nodes; the remainder of the examination was unremarkable.

A contrast-enhanced computed tomography (CT) scan of the neck, chest, abdomen, and pelvis was performed, and multiple lung nodules with mild hepatomegaly and homogenously hyperenhancing soft tissue density lesions in bilateral kidneys with partial encasement of renal vessels and proximal ureters were found. No hydronephrosis, paranephric extension, renal vein invasion, or thrombosis was noted. Positron emission tomography-computed tomography (PET-CT) showed bilateral FDG avid lesions in both kidneys, left lesion measuring 7.8 × 5.6 cm, SUV 5.2, and right lesion measuring 7.2 × 5.2 cm, SUV 4.5. The metabolically avid cervical and abdominal lymph nodes were also found, mimicking lymphoma (Figs. 1, Fig. 2, Fig. 3). The renal function profile of the patient was within the normal range.

Fig. 1.

(A) axial CT image shows hypovascular bilateral renal masses (white arrows). No perinephric extension or renal vein invasion. (B) PET CT image & (C) fused images revealed hyper-metabolic bilateral renal masses (white and black arrows).

Fig. 2.

(A) PET CT & (B) fused PET CT images show hypermetabolic enlarged cervical lymph nodes (black and white arrows).

Fig. 3.

MIP image of PET CT showing hypermetabolic bilateral renal masses (white arrows), and multifocal marrow uptake in proximal femora and humeri (black arrows).

The patient had undergone an ultrasound-guided renal biopsy. On histopathological examination, the sheets of large histiocytes exhibited emperipolesis (Fig. 4). Immune-histochemical staining was positive for S100 and CD68 but negative for PAX8 and CK (Fig. 5). The patient was diagnosed with Rosai-Dorfman Disease.

Fig. 4.

Histopathological slide of the left renal mass shows severe chronic inflammatory infiltrate (lymphocytes, plasma cells, histiocytes) surrounded by areas of fibrosis and degenerated cells.

Fig. 5.

Immunohistochemical marker, CD20: specimen highlighting scattered B-cells CK8/18, CK & ALK negative CD3: PAX8: positive in reactive T-cells, PAX8 highlighting inflammatory cells, trichrome: highlighting few areas of fibrosis, CD68: positive in histocytes.

The chemotherapy regimen comprising cyclophosphamide, vincristine, and prednisone (CVP) was advised to the patient. The systemic therapy was used as the patient had a multisystemic disease with renal and bone marrow involvement. A total of 6 cycles of CVP were given, and steroids were tapered off slowly. A PET-CT was repeated after completion of chemotherapy. However, the bilateral renal masses remained stable in size, along with a decrease in lymph node size, indicating a partial treatment response (Fig. 6). Renal function profile also remained normal. The patient was followed at an interval of 6 months, and his symptoms of fatigue and weakness improved clinically (Table 1).

Fig. 6.

Post treatment PET CT revealed interval decrease in size and avidity of bilateral renal masses.

Table 1.

Summary of previously reported cases of renal RDD.

Study	Presentation	Management	Outcome
Aziz El Majdoub et al. [20]	A 68-year-old female presented with hematuria and flank pain, diagnosed with a right renal mass invading the right renal vein; radiology mimicked renal cell carcinoma.	Open radical nephrectomy, adrenalectomy, and lymphadenectomy.	Benign RDD on pathology; outcome not fully detailed but described as “unusual benign entity”.
Bassa et al. [21]	A 64‑year‑old woman presented with diffuse abdominal pain; RDD with renal involvement and secondary glomerulopathy; kidney involvement was noted as a poor prognostic factor.	Managed with corticosteroids and remained on regular follow-up.	Patient improved without any new episodes of extrinsic urinary compression or complications.
Danisious et al. [22]	A 12‑year‑old girl presented with low-grade fever and cough; diagnosed with a left renal mass, para‑aortic and retroperitoneal lymphadenopathy, and hydronephrosis, associated with cold‑type autoimmune haemolytic anemia.	Systemic steroids first; inadequate response followed by chemotherapy.	Marginal response to chemotherapy.
Abrishami et al. [23]	A 67-year-old asymptomatic female presented with a raised serum creatinine level and erythrocyte sedimentation rate (ESR) on routine follow-up.	Right partial nephrectomy and left radical nephrectomy with a small residual mass remaining due to technical difficulties of complete resection.	RDD confirmed on histopathology, renal function was preserved.
Nallabothula et al. [24]	A 63-year-old male presented with left flank pain. Extranodal renal hilar mass infiltrating medulla and cortex; imaging suggested renal cell carcinoma; associated retroperitoneal and para‑aortic nodes.	Laparoscopic left radical nephrectomy along with removal of proximal ureter and para-aortic lymph nodes.	Pathology confirmed extranodal renal RDD; outcome not fully detailed.
Kushwaha et al. [25]	A 75-year-old female presented with right flank fullness and pain. PET‑CT showed two lobulated solid renal masses mimicking carcinoma.	Radical nephrectomy.	Histopathology confirmed renal RDD: postoperative course not specified.
Lu et al. [26]	A 67‑year‑old man, asymptomatic, with a bilateral perinephric “hairy kidney” with a large left renal mass; renal function preserved.	Percutaneous ultrasound-guided biopsy was performed of the left renal mass.	Histopathology and immunohistochemistry confirmed RDD; remains asymptomatic without additional treatment on follow‑up.

Discussion

Overview and epidemiology

RDD is a rare, idiopathic non-Langerhans cell histiocytic disorder. Destombes initially described it in 1965, and later on by Rosai and Dorfman in 1969. RDD had been classified as “R Group” of histiocytosis and is a heterogeneous syndrome with various prototypes, including sporadic, familial, and non-cutaneous, non-Langerhans cell RDD [4]. The sporadic RDD can be further classified into classic nodal-involved, extranodal, immune disease-associated, and neoplasm-associated RDD. The prevalence of RDD is approximately 1:200,000, with a higher morbidity [5]. It commonly manifests in children and young adults with a male predominance. RDD typically presents with massive cervical lymphadenopathy along with constitutional symptoms such as fever, malaise, and weight loss. In this case, a male presented with constitutional symptoms and cervical lymphadenopathy.

Extranodal and renal involvement

Extranodal involvement of RDD is present in about 40% of cases and the most commonly identified extra-nodal sites were skin and soft tissue (16%); nasal cavity and paranasal sinuses (16%); eye, orbit, and ocular adnexa (11%); bone (11%); salivary gland (7%); central nervous system (7%); oral cavity (4%); kidney and genitourinary tract (3%); respiratory tract (3%); liver (1%); tonsil (1%); and breast (<1%) [6]. Only 4% of cases involve renal dysfunction, and different studies have different opinions about the prognosis of kidney RDD. Our follow-up data showed renal involvement, which is a benign lesion, similar to Lai et al., that multi-organ involvement was present in just 19% of RDD patients. Renal RDD can result in hematuria, abdominal fullness, flank pain, ureteral obstruction, or nephrotic syndrome brought on by renal vein thrombosis [7,8].

Radiological features

Even though RDD is usually benign and self-limiting, it can be difficult to diagnose and distinguish from malignant and inflammatory conditions due to its multiple clinical manifestations and non-specific imaging results. Radiologically, RDD can present as numerous low-density lesions in both kidneys on enhanced CT, along with bilateral diffuse renal enlargement, a hypovascular solitary renal mass, and hypertrophic lesions affecting the renal pelvic wall with a regular renal pelvic surface [6]. On PET-CT, RDD lesions are typically FDG-avid, reflecting high metabolic activity, further complicating the differentiation from the malignant process [9]. The primary differential diagnosis is renal lymphoma, characterized by bilateral homogenous masses and significant retroperitoneal lymphadenopathy; however, it often exhibits a more uniform and less infiltrative pattern [10]. Renal metastases can present as multiple bilateral lesions; nonetheless, they are often well-defined and associated with an identified source tumor. IgG4-related disease may present as renal cortical nodules or perirenal soft tissue thickening, frequently associated with systemic involvement, including pancreatitis and high IgG4 levels. Erdheim–Chester disease (ECD), a histiocytic illness, is characterized by perirenal infiltration resulting in the “hairy kidney” appearance, as well as skeletal and cardiovascular involvement. Xanthogranulomatous pyelonephritis is generally unilateral, linked to obstruction and infection, and exhibits characteristics such as the “bear paw sign.” Despite these differences, considerable imaging overlap persists, and a conclusive diagnosis depends on histological evaluation [11].

Histopathology and immunohistochemistry

Histopathology remains the diagnostic cornerstone of the RDD. Morphologically, RDD is characterized by histiocytes with enlarged round-to-oval nuclei, prominent nucleoli, light nuclear chromatin, and abundant pale cytoplasm, often accompanied by frequent engulfment of inflammatory cells, known as emperipolesis. In emperipolesis, lymphocytes are not attacked by enzymes and appear intact within histiocytes, a specific and diagnostic feature of RDD [12]. Extranodal disease typically presents as a histological background displaying a variable degree of fibrosis and inflammatory infiltrate, potentially obscuring the abnormal RDD histiocyte population. Scattered lymphoid follicles are often noted, and plasma cell infiltrates are a common feature, frequently arranged perivascularly [13]. Immunohistochemistry has a significant role in the diagnosis of RDD. RDD histiocytes consistently express S100 protein, CD68, and CD163, which confirms their histiocytic origin. Other positive markers include CD14, fascin, PU.1, Oct-2, α1-antichymotrypsin, and α1-antitrypsin, indicating lysosomal and phagocytic activity. RDD is negative for Langerhans cell markers such as CD1a and langerin, along with follicular dendritic cell markers, aiding in its differentiation from Langerhans cell histiocytosis and other similar conditions [4,14].

Pathogenesis

The exact pathogenesis of RDD is still unknown. It has been suggested that infections with human herpes virus-6, Epstein–Barr virus, and Parvovirus B19 may trigger the disease [15]. Several genetic mutations have been discovered linked to RDD, including ARAF, MAP2K1, NRAS, and KRAS. RDD has also been reported in association with autoimmune diseases and lymphomas [4].

Management

The management of RDD is individualized, varying among patients, and resolves spontaneously in approximately 20% to 50% of cases. Observation could be appropriate for asymptomatic patients with stable disease. However, some patients may develop organ dysfunction as a result of extensive nodal enlargement, which can result in a fatal disease [8]. In such circumstances, it is crucial to initiate treatment to impede the natural progression of RDD. Systemic or local steroids are frequently used for symptomatic patients with a response rate of 50-60%, but relapse rate is common. Systemic chemotherapy has proven to be effective for patients with refractory, recurrent, or multisystem diseases, employing agents such as vinca alkaloids, alkylating agents, anthracyclines, and antimetabolites [4]. Moreover, additional treatment options include immunomodulatory therapies, targeted agents, and radiotherapy for localized diseases. Surgery is indicated only for local and accessible lesions [7].

Prognosis

RDD is typically considered a benign and self-limiting condition; however, multisystem involvement can lead to considerable morbidity and even mortality. Fatal outcomes are generally associated with critical organ involvement rather than the disease itself. Cardiovascular complications may arise from perivascular infiltration or retroperitoneal fibrosis, resulting in vascular compression and impaired blood flow [16,17]. Involvement with the central nervous system may lead to mass effect, neurological impairments, or elevated intracranial pressure. Pulmonary manifestations, such as interstitial lung disease or pulmonary hypertension, may lead to respiratory compromise. Renal involvement, especially when bilateral or accompanied by ureteric obstruction, may result in progressive renal insufficiency or failure. Consequently, identifying organ-threatening diseases is essential, since prompt intervention can avert life-threatening consequences and enhance overall prognosis [3,8].

Differential diagnosis

Xanthogranulomatous pyelonephritis (XPG), leukemia, lymphoma, and lymphadenopathy are the differential diagnoses of renal RDD. Other potential differential diagnoses might include storage diseases, histiocytic infiltration related to infectious diseases such as tuberculosis, or even renal carcinoma [3]. ECD is a significant differential diagnosis for multisystem involvement with renal masses, due to its similarities with RDD, a non-Langerhans cell histiocytosis characterized by CD68 positivity and CD1a negativity [18]. It generally manifests as symmetric osteosclerosis of long bones, cardiovascular complications such as “coated aorta,” and perirenal infiltration characterized by “hairy kidney” [18]. Histologically, it exhibits foamy histiocytes, Touton giant cells, and prevalent BRAF V600E mutations, while RDD is distinguished by emperipolesis and S100 positivity [19]. Precise distinction necessitates the correlation of imaging, histology, and immunohistochemistry.

Conclusion

RDD is a rare and diagnostically challenging disease presenting with a wide range of clinical symptoms, especially in extranodal RDD. Renal involvement by RDD is uncommon and may mimic malignancy on radiological imaging, emphasizing the significance of histopathological and immunohistochemical evaluation for definitive diagnosis. This case highlights the need to include RDD in the differential diagnosis of bilateral renal masses with systemic lymphadenopathy. Early diagnosis and appropriate management can prevent disease progression. The reporting of such atypical presentations is important to improve awareness, facilitate early diagnosis, and optimize treatment.

Authors’ contributions

Nadia Nazir conceived and designed the case report. Nadia Nazir and Fatima Israr were responsible for data collection and acquisition of data. Nadia Nazir performed the literature review and wrote the manuscript. Anis Ur Rehman, Aasma Ashraf and Kashif reviewed and critically revised the manuscript. All authors have approved the final manuscript.

Patient consent

A written informed consent was obtained from the patient for the publication of this case report.