Rosai-Dorfman Destombes Disease

Defnition

Rosai-Dorfman Destombes disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a very rare histiocytic disorder involving the proliferation of histiocytes with a macrophage-dendritic cell phenotype. RDD presents most commonly with painless lymphadenopathy and is characterized by emperipolesis on histology [1, 2, 11].

Epidemiology

RDD is a rare disorder with a prevalence ~1/200,000 that typically affects young adults and adolescents [4, 11], although it has been documented in all age groups [11]. A systematic review by Moyon et al. endorsed a median age at diagnosis of 45 years old [34]. There is limited evidence of a predilection for males and people ofAfrican descent, although epidemiologic data are sparse and not conclusive [11].

Etiology/Pathophysiology

The etiology of RDD is unknown and is thought to be multifactorial [11]. It has been suggested that viral infections such as herpes simplex virus and human immunode ciency virus, lymphomas or other lymphoproliferative and autoimmune disorders, systemic lupus, IgG4 disease, amyloidosis, or polycythemia vera may be associated with the development of RDD [11]. Inherited conditions linked to RDD, include those due to mutations in SLC29A3 and TNFRSF. Similar to PLCH and ECD, there is mounting evidence that RDD is a neoplastic histiocytic disease linked to mutations in the MAPK/ERK pathways. Studies have demonstrated mutually exclusive ARAF, KRAS and MAP2K1 mutations in one-third of cases of RDD [5, 35] as well as positive staining for phosphorylated ERK (an indication of excess MAPK signaling) in 90–100% of cases examined [36, 37]. Detection of ­BRAF-V600E mutations may require very sensitive testing methods [2, 38].

Histopathology and Immunohistochemistry

The histopathologic features of RDD include tissue in ltration by large histiocytes that are characterized by extremely pale eosinophilic cytoplasm with a large hypochromatic

a

c

nucleus and notable nucleolus with an infammatory background comprised of numerous polytypic plasma cells, with or without lymphoid follicle formation and small neutrophilic in ltrates [1, 4, 11] (Fig. 16.13). The pathognomonic feature of RDD is emperipolesis; the nding of histiocytic

b

d

Fig. 16.13  Pathology of Rosai Dorfman Destombes Disease (RDD). (a) The lung is an uncommon location for RDD. Rather the lymph nodes may be more commonly involved with massive sinus expansion. When the disease progresses, the lesional cells may be obscured by abrotic stromal background that may mimic ECD in extranodal sites, as emperipolesis may be less pronounced in these locations (a, digital scanned H&E, 7.5×). The diagnostic RDD cell is a large histiocyte with

ample pale lightly vacuolated cytoplasm and a large nucleus with hypochromatic chromatin and small but prominent nucleoli (b, digital scanned H&E, 40×). The S100 immunostain (c, d digital scanned immunostain, c, 5× and d, 40×) will best bring out the large cells with nuclear and cytoplasmic staining and evident negative staining refection of the traf cking leukocytes (emperipolesis)

cells containing intact infammatory and erythroid cells (leukocytes, erythrocytes, and plasma cells) within their cytoplasm; however, it is not mandatory for diagnosis and often scant in extranodal sites as compared to nodal sites [2, 4, 6, 11]. On the other hand, the degree of emperipolesis may be so great as to obscure the large hypochromatic nucleus of the RDD cells such that immunostains including S100 and fascin may better highlight the non-staining traf-cking cells within the large stained RDD cells. Unlike PLCH and ECD, the histiocyte in RDD has a characteristic large-sized, unique monocyte/macrophage to dendritic cell type phenotype. Ranvindran et al. have recently identi ed OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD as it was expressed in 97% of their tested RDD cases [39]; however, this is not speci c to RDD and can be also seen in other histiocytic neoplasms, including malignant cases, and some LCH cases. Other markers useful in the diagnosis of RDD include S100, CD163, and cyclin D1. Like most histiocytic neoplasms, cyclin D1 is also often expressed with nuclear and cytoplasmic staining and phos- pho-ERK can show variable expression in the large RDD cells. RDD cells are negative for CD1a, langerin, and factor XIIIa [1, 4, 11, 20, 39].

Clinical Presentation

Patients typically present with painless bilateral lymphadenopathy, most commonly involving the cervical region, occasionally associated with constitutional symptoms including pyrexia and weight loss [4, 11]. While extranodal manifestation occurs in up to 40% of patients, pulmonary involvement is rare (less than 5% of cases) [2, 20], typically involving the large airways and sinuses, or the lung parenchyma [2, 4]. The most common pulmonary manifestation is that of polypoid masses involving the major airways with associated mediastinal or hilar adenopathy that can mimic sarcoidosis in radiographic appearance [20, 34]. Less commonly, interstitial expansion, parenchymal nodular lesions, pleural nodules, pleural effusion, or diffuse interstitial thickening may be seen [2, 4, 20] (Fig. 16.14). Lesional involvement of the airways produces the most common symptoms of chronic dyspnea, which can be severe dry cough, stridor, or hoarseness. Lesions within the airways may cause obstructive defects in spirometry [11, 34]. Although lower respiratory tract involvement can have an aggressive course, it is unusual for RDD to result in acute respiratory failure or cor pulmonale [2, 34].

Fig. 16.14  Radiographic ndings of pulmonary RDD. (a) Lung windows in a middle-aged man with Rosai-Dorfman Destombes disease. Contrast enhanced chest CT in lung windows reveals mild diffuse ground glass opacity, septal lines, and ssural thickening. (b). Mediastinal windows show paratracheal lymphadenopathy. (Case courtesy of Seth Kligerman, M.D. San Francisco, CA.). 53 years old man who presented with inguinal lymphadenopathy and periorbital eye swelling. (c) Contrast enhanced orbit CT periorbital and preseptal and right lacrimal gland soft tissue in ltration. (d) Contrast enhanced chest

CT reveals bilateral hilar and subcarinal adenopathy. A right pulmonary artery pulmonary embolus (yellow arrow) is also present. (e) Contrast enhanced abdomen CT reveals low attenuation mass in the spleen (black arrow), left kidney (white arrow), duodenal in ltration (black arrowhead), and retroperitoneal adenopathy (white arrowhead). (Different images of this case were previously published in Ahuja J, Kanne JP, Meyer CA, et al. Histiocytic Disorders of the Chest: Imaging Findings. RadioGraphics 2015; 35: 357–370)

Pulmonary involvement is almost always accompanied by evidence of multisystem disease [34]. Other extranodal sites that can be involved in RDD in order of frequency include skin, nasal cavity, upper gastrointestinal tract, bone, orbits, central nervous system, genitourinary system, and rarely, (<5%) hepatic or pancreatic involvement [11]. A retrospective study of Mayo Clinic records performed in 2010 examined patients with histopathologic evidence of RDD on organ biopsy; 9 of 21 patients diagnosed with RDD had intrathoracic manifestations (43%) with the primary pulmonary symptoms being dyspnea and cough. Mediastinal lymphadenopathy (6 patients) was the most common radiographic manifestation while cystic change, interstitial lung disease, and airway disease were radiographically evident in 4 patients [40] (Fig. 16.14).

Investigation/Diagnosis

ultrasound and biopsy may be a useful diagnostic tool in RDD, given mediastinal adenopathy is often easily accessible with this technique. Bronchoalveolar lavage may demonstrate macrophage alveolitis [34], but this is non-speci c. Transbronchial biopsy of lesions demonstrated on CT chest may be sent for pathologic examination and reveal histologicndings of RDD [34]. As with other histiocytic diseases, tissue sampling with histopathology and immunohistochemical evaluation is the gold standard for diagnosis, in the case of RDD demonstrating large cells that are S100 positive, and CD1a, langerin, and factor XIIIa negative [2, 4, 20].

In general, the diagnostic strategy for RDD is very similar to that of ECD and LCH. However, as RDD does not typically involve the endocrine system, evaluating for endocrinopathies as part of staging is usually unnecessary.

Management/Treatment

A high index of suspicion is necessary to diagnose RDD, as there is often very little physical examination (beyond lymphadenopathy) or on laboratory evaluation to suggest the diagnosis. Plain lms obtained as part of the initial investigation are typically non-speci c but may demonstrate mediastinal widening. CT of the chest may be helpful in evaluating lesions and guiding the optimal site for biopsy. The most common features of CT are mediastinal and hilar adenopathy [1]. Although less common, parenchymal nodules, interlobular septal thickening, thin-walled cysts, ground glass opacities, and poorly de ned lung nodule(s) or masses may be seen [4, 11, 34]. There may be single or multiple nodular masses of the trachea and bronchi involving the adjacent fat and associated with varying degrees of airway obstruction [11]. PET-CT can be utilized as RDD lesions are metabolically active [11], and affected lymph nodes exhibit a halo appearance related to concentration of the most intense radiotracer uptake within their centers [4] (Fig. 16.14).

As with ECD and PLCH, pulmonary function tests in RDD may be normal or may demonstrate obstructive, restrictive, or diffusion defects depending on the nature of pulmonary involvement [34]. Bronchoscopy with endobronchial

Treatment strategies for RDD are similar to the other histiocytic neoplasms and must be tailored to individual clinical circumstances as outlined in Fig. 16.15. Given that many patients remain asymptomatic with stable radiologic ndings, or even experience spontaneous regression in 20–50% of cases, a conservative approach without intervention may be appropriate [1, 11]. In patients who are symptomatic, there are anecdotal reports of the use of the purine analog, cladribine [1], resulting in improvement in lung involvement on PET-CT [34], as well as reports of good responses to glucocorticoid therapy [11]. Moyon et al. described the use of cobimetinib, a MEK 1 and 2 inhibitor, in patients with RDD that exhibited KRAS mutations without detectable MAP kinase pathway mutations [24]. The only noted adverse effect was an acne-like rash.

There are reports of progression of RDD with the use of pegylated IFN-α [34], and limited or no responses with methotrexate, azathioprine, rituximab, vinblastine, cytarabine, infiximab, and/or combinations of these therapies [11, 34]. There are also reports of surgical, endoscopic, or laser debulking of adenopathy, together with adjuvant radiation therapy although ef cacy is unclear [34].