CUTANEOUS ROSAI-DORFMAN DISEASE – A CLINICAL CASE

Virgil Pătrașcu1, Alexandra Filculescu1, Corneliu Cristian Georgescu2, Raluca Niculina Ciurea3 1Dermatology Department, Emergency County Hospital, Craiova, University of Medicine and Pharmacy of Craiova, Romania 2Clinic of Anesthesia and Intensive Therapy, Emergency County Hospital, Craiova, University of Medicine and Pharmacy of Craiova, Romania 3Pathology Department Emergency County Hospital, Craiova, University of Medicine and Pharmacy of Craiova, Romania


Introduction
Rosai-Dorfman disease (RD) is a benign condition of unknown etiology (1), characterized by selflimiting proliferation of non-Langerhansian histiocytes inside lymph nodes but also in extranodal areas (1,2).

Clinical Case
A 54-year-old patient from a rural region is hospitalized in our Dermatology Department for a polymorphous rash composed of violet-erythematous papulonodules with sizes ranging between 0.2 cm and 2 cm, slightly itchy, located in the latero-thoracic region, lumbar region and in the area around the menton area.No family history to mention.
Disease history.The patient was hospitalised in the Dermatology Department of Craiova Hospital in March 2016, when he reported that the symptomatology appeared 18 months prior to hospitalisation.Initially, the lesions where localized in the menton area, later developed in the right laterothoracic level (Figure 1) and left lumbar region (Figure 2).Outpatient treatment was composed of general treatment with hydrocortisone hemisuccinate, loratadine and diclofenac, and locally with fusidic acid and hydrocortisone, alternating with methylprednisolone acetonate cream, with no favorable evolution.
Patient examination: medium general state, overweight, type 3 phototype, nocturnal paresthesias of the hands, pain in the lumbar spine region and right knee, nycturia and slowed bowel movements.
Paraclinical investigations.Laboratory investigations (CBC, biochemistry, ESR) were all within normal limits, except for a 4% eosinophilia and dyslipidemia (high level of triglycerides: 245 mg/dL), and the serology for Hepatitis B and C were both negative.Serology for HIV and Treponemic infection were negative too.
Histopathological examination (Hematoxylin-Eosin staining) showed lymphoid structures in the dermal region, composed of histiocytes, lymphocytes, plasma cells, with nodular or insular disposition, which filled the dermis completely, some reaching even the hypodermis.The cells had large nucleus, round or ovular in shape, vesicular and with an abundant eosinophilic cytoplasm (Figure 3 and 4).Emporipolesis was found (Figure 5): histiocytes that ingest inflammatory cells, a characteristic phenomenon of cutaneous Rosai-Dorfman disease, which can support the diagnosis.
Imunohistochemical tests revealed:   6. S100 protein positive in frequent histiocytes, some with emperipolesis.Chest X-ray did not show any active pleura-pulmonary processes, the heart was within normal limits, aorta with higher opacity.No images of possible secondary determinations were captured.
Abdominal and pelvic ultrasound: liver with a left lobe antero-posterior diameter of 7.7 cm, and a right lobe diameter of 13.5 cm, normal echogenicity, homogenous, without localized processes; gall bladder with thin walls, no stones; portal vein and primary biliary route of normal diameter; right kidney 11 cm in long axis, 4 cm transverse, parenchyma index of 15 mm, no stones, no dilations, vascularisation present; homogenous spleen, long axis of 10 cm; left kidney similar with the right kidney; hyperechogenous pancreas, relatively homogenous, normal sized; the bladder was empty, hard to visualize, with no liquid in the peritoneal cavity.
CT scan of the chest and abdomen: liver with a 1.8 cm image in the 7 th segment subcapsular, spontaneous hypodens, well defined, with vascular capture in arterial phase and a tendency towards homogenization, which could be the expression of a capillary hemangioma; spleen 9/4.9 cm, with no retroperitoneal lymphadenopathies and no fluid in the abdominal cavity.
After ophthalmological and neurological exams, other localizations of the disease had been excluded.Hematological examination did not find any pathology.
Corroborating medical history with clinical manifestations and paraclinical investigations, we established the diagnosis of cutaneous Rosai-Dorfman disease.Treatment was based on Doxycycline 100 mg, first two capsules a day for a month and then 100 mg/day for three months, and a combination of Rutoside 20 mg and ascorbic acid 50 mg (three capsules a day), Pentoxifylline 400 mg twice a day and Levocetirizin 5 mg/day.The patient's evolution was slightly favorable and therefore he was discharged.

Clinical study
After three months from discharge, the patient was readmitted to our Dermatology Department for reevaluation and extrainvestigations.Patient examination revealed disappearance of the lesions in the thoracic area (Figures 6 and 7).Laboratory analysis and inflammatory markers were within normal limits.

Discussion
Rosai-Dorfman disease was first described by Destombers in 1965 (1), and a year later by Azoury and Reed.In 1969, Juan Rosai and Ronald Dorfman reported a histiocytic affliction developed on a young black male, who presented with a massive cervical lymphadenopathy, bilateral, with no pain, associated with fever, anemia, neutrophilia, a high ESR and policlonal gamapathy.The above-mentioned authors called this entity Sinusal Histiocytosis with Massive Lymphadenopathy (SHML).Given that lymphadenopathy does not appear in extranodal localizations, the term of SHML becomes incorrect, which is the reason why the eponym of Rosai-Dorfman is encouraged to be used (2).

Epidemiology
Rosai-Dorfman disease is a rare condition, with a prevalence reported at 1:200 000 people.It affects primarily males (58% males, 42% females), being more frequent in young adults and people of African descent.In the literature, patients' age varied widely from one year old to 74 years old (3).
Approximately 13% of patients with Rosai-Dorfman disease associate immune afflictions such as uveitis, lupus erythematous, rheumatoid arthritis, hypothyroidism and lymphomas (1).The most frequent association is with uveitis, which does not affect the disease prognostic, but increases morbidity (4).
The Pathogenesis of Rosai-Dorfman disease is not fully understood, although a disorder of the cell mediated immunity (5), immune factors and infections can play an important role (6).The polyclonal nature of the cellular infiltrate and the clinical progression of Rosai-Dorfman disease suggest rather a reactive process than a neoplasic one (7).In an article published in 1999, Middel et al. found that monocyte and macrophage stimulation by the macrophage colony stimulation factor (M-CSF) generated immunosupresive macrophages.It appears that immunosuppresive macrophages represent the primary mechanism in the pathogenesis of Rosai-Dorfman disease (8).Six years later, Mannan et al. published a study in which they proposed that the dendritically cell would be the basis of origin of Rosai-Dorfman disease (9).
In some cases it was noticed that human herpes virus 6 (HHV 6) and Ebstein-Barr virus (EBV) are associated with the pathogenesis (10).Luppi identified the expression of viral antigen of HHV 6 in two cases of Rosai-Dorfman disease (11).Also, Levine et al. published a study in which they used in situ hybridization to detect HHV 6 in patient tissue (10).Rarely, it can be associated with Brucella, Klebsiella rhinoscleromatis and Nocardia, although numerous studies could not confirm this association (1).
Histicytosis represent a group of diseases characterized by histiocyte hyperproliferation.Histiocytes derive from the mononuclear phagocyte system, are capable to stock lipids and have a esterase, phosphates and lysozyme rich cytoplasm.They are antigens presenting cells towards lymphocytes, intervening in antibody and cellular mediated immune reactions, and ultrastructuraly possess Birbeck granules (12,13).
The World Health Organisation (WHO) classifies the lesion in a class II of histiocytosis syndromes, while The American Society for the Study of Histiocytosis places this entity in the group of macrophage conditions (2).
Foucar divided this disease in three subtypes: nodal, extranodal type and mixed (with organic and lymph node implication) (4).Extranodal types represent 43% of all cases of Rosai-Dorfman disease (15).
The superior respiratory tract is the most frequently affected, followed by the skin, eyes, retroorbital tissue and bone tissue.Salivary glands and Virgil Pătrașcu, Alexandra Filculescu, Corneliu Cristian Georgescu , Raluca Niculina Ciurea Cutaneous Rosai-Dorfman disease was described for the first time by Thawerani et al. in 1978, when they reported the case of a 48-year-old patient who presented for a nodule in the capsular region and hypergammaglobulinemia (16).The cutaneous form is rare, representing 3% of all cases of extranodal type Rosai-Dorfman disease.Until the year 2008 there have been 80 reported cases.It is more frequent in females (sex ratio 2/1) and in adults with Asian descent, with a mean age of 45 years.
Clinically, cutaneous Rosai-Dorfman disease is characterized by the presence of papule, no du les, plaques or tumors, light brown, dark brown or violet-red in color, with sizes ranging from 1 to 30 cm, localized or disseminated.The lesions most often appear in the head and neck region, in the thoracic region and later towards the extremities.The lesions could sometimes resemble acne or psoriasis (17).
When cutaneous Rosai-Dorfman disease is suspected, it is important to exclude other histiocyte disturbances, especially Langerhans cell histiocytosis, which is a potentially lethal disease.Langerhans cell histiocytosis presents with cells with "coffee bean" nucleus; electronic microscopy can observe the Birbeck granules, and immunohistochemical tests are CD1a positive.The inflammatory infiltrate is rich in eosinophiles and lymphocytes, but with the absence of emperipolesis.It is considered that any histiocytary lesion with rich eosinophiles infiltrate needs immunohistochemical studies to exclude histicytosis with Langerhans cells (18).
Xanthogranulomatous conditions can present with a large variety of morphological characteristics, including vacuolated xanthomatous mononuclear cells with a tree-like appearance, patognomonic for juvenile xantogranuloma, or can present with neoplastic alteration in adult xanthogranuloma.Although giant multinuclear cells are present and help in classification of the conditions (giant Touton type cells in juvenile xanthogranuloma and giant Langhans cells in adult xanthogranuloma) these are not patognomonic.Giant multinucleated cells and also foamy histiocytes can also be observed in cutaneous Rosai-Dorfman disease.Thus, the presence or absence of emperipolezis is the most important histological characteristic which can help in distinguishing between the two diseases.
Also immunohistochemical studies can confirm the diagnosis, because xanthogranulomatous diseases are usually positive for factor XIIIa, CD68, CD163 and CD14, and negative for CD1a and protein s100 (18).
Differentiation between cutaneous Rosai-Dorfman disease and reticulohistiocytoma cutis is really difficult, because histiocytes from reticulohistiocytoma may present positive protein S100, but the ground-glass aspect of the histiocyte with rich cytoplasm, absent plasma cells and diffuse of emperipolesis may help to differentiate between the two entities (1).
Cases of malignant histiocyte conditions must also be excluded, including Histiocyte sarcoma, which is considered to be an extremly aggressive tumour.Foamy cells in the shape of a tree are present, though many of the histiocytes show a high grade of atypical shapes.Diagnosis is supported by the presence of CD68, which is accompanied any positive staining of lysozyme in 80% of cases.
Cases were reported of histiocyte sarcoma which began on the basis of a preexisting Rosai-Dorfman disease, although these cases were very rare.The characteristics of differentation between the two entities are: cellular atypia, pleomorphism, invasion and destruction of tissues (18).

Treatment
Because cutaneous Rosai-Dorfman disease is characterized as a benign self limiting condition, with some cases in which spontaneous resolution is observed after months or years, therapy is recommended to be less aggressive.Surgical excision is recommended when the lesions are localized.
Favorable results have been obtained in some patients treated with Vinca alkaloids, tetracyclines and alchilation agents.
In a study by Pulsoni et al. in 2002, on a group of 12 patients, two of the subjects had favorable treatment response using 6-mercaptopurine and methothrexate (20).
A case was reported of a 8-year-old boy presenting with a massive, painful lymphadenopathy that had begun three weeks prior, and was successfully treated with 2-chlorodeoxiadenozine, when conventional treatment (clarithromicine, doxycycline, augmentin and corticosteroids) had failed (20).
Jian-Xin Xia et al. have reported two cases, both of Asian descent, of cutaneous Rosai-Dorfman, respectively a 46-year-old woman, who presented with multiple papules and nodules on the left cheek that lasted for 10 years, and a second woman, aged 57, who presented with an itchy erythematous plaque that began seven months earlier.Histopatological and immunohistochemical studies confirmed the diagnosis of cutaneous Rosai-Dorfman disease.The lessions improved after interlesional treatment with metamethazone and lidocaine, intramuscular interferon and oral acitretin, with no recurrence after an observation time of one year (21).

Figure 3 .
Figure 3.In the dermal region, lymphoid structures, composed of histiocytes, lymphocytes, plasma cells, with nodular or insular disposition, which filled the derma completely, some reaching even the hypodermis, Hematoxylin-Eosin staining, x40

Figure 4 .Figure 5 .
Figure 4.In the dermal region, lymphoid structures, composed of histiocytes, lymphocytes, plasma cells, with nodular or insular disposition, which filled the derma completely, some reaching even the hypodermis, Hematoxylin-Eosin staining, x40