Meningeal Form of Rosai-Dorfman Disease

Introduction

General characteristics

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare disease characterized by nonmalignant proliferation and accumulation of a specific type of leukocytes (histiocytes) predominantly in lymph nodes, but it can also accumulate in other localizations throughout the body [1–3]. The record of the first four cases of this disease dates back to 1965 and was described by French pathologist Pierre Paul Louis Lucien Destombes [1]. From 1969 to 1972 pathologists Juan Rosai and Ronald Dorfman analyzed 34 cases of the same entity and called it sinus histiocytosis with massive lymphadenopathy [2–3]. Since then, more than 1,000 cases of RDD disease have been described in the literature. This disease affects both male and female (although some sources report higher incidence in male) of all age groups, depending on form of RDD, but most likely in children, adolescents and young adults under the age of 20 [4–6].

Etiology

The exact cause of RDD remains unknown. Infections may attribute to disease onset and many pathogens (Klebsiella, polyomaviruses, Epstein-Barr viruses, parvovirus B19, human herpesvirus 6 and HIV) are discussed as a possible cause of the disease. Although these associations with various infection agents have been reported, these findings may represent simple harboring of these infective agents in lymphocytes or macrophages with no relation to etiology. Other factors involved may be attributed to immunodeficiency, environment or autoimmune diseases. Inflammatory activated monocytes can produce colony-stimulating factor for macrophages, resulting in complex signal transduction, which subsequently leads to the histopathology characteristic of RDD [7–8]. There is a significant increase in rheumatologic disorders and hemolytic anemia among these patients [9]. Recently mutations in oncogenes with kinase activity as NRAS or KRAS were found in patients with RDD [10–11]. A specific germ line mutation in the FAS gene is responsible for the autoimmune lymphoproliferative syndrome type I, which may be associated with RDD [12–14]. Therefore, in general we can distinguish RDD associated with inherited conditions, neoplasia associated RDD and immune-related RDD.

Clinical picture

In some cases, RDD can be asymptomatic. Symptoms are very variable and individual, depending on the affected organ. The most common symptoms include painless bilateral cervical enlargement of the lymph nodes, and general symptoms, such as fever or weight loss [3,6,8,15]. The nodal form occurs in 60% (with predominant damage of cervical lymph nodes), the extranodal form occurs in remaining 40% with various organs affected, such as nasal and paranasal cavities (11%), eyes/eyelids/orbit (11%), bones (9%), salivary glands (isolated form) (5%) and CNS (7%), in rare cases kidney (2%), respiratory tract or liver [16].

Diagnostics

Possible laboratory findings are anemia, leukocythemia, neutrophilia, high sedimentation and polyclonal hypergammaglobulinemia [3,6,8,15]. The differential diagnosis of meningenial form of RDD is broad, including inflammatory and neoplastic lymphohistiocytic condtions (abscess, inflammatory pseudotumor, tuberculosis, plasma cell granuloma, sarcoidosis, Langerhans cell histiocytosis, Hodgkin’s lymphoma), tumors (meningioma – the most common differential diagnosis, glioma, germinoma), metastasis and chronic subdural hematoma [17–20].

Therefore, the most important diagnostic method is biopsy of the affected tissue with microscopy and immunohistochemistry. Microscopic findings are lymphocyte infiltration, histiocyte character and multinuclear cells presence and typically emperipolesis (passage of every blood element through cytoplasm of histiocytes without damage). Immunhistochemical findings are S100, CD68, CD163, CD14 and MAC-387 positivity and CD1 and CD21 histiocyte negativity [7,21]. Any cause of lymphadenopathy, such as infections, lymphomas, leukemias, melanoma and other malignancies and Gaucher disease should be ruled out by biopsy. The sinuses of reactive lymph nodes contain histiocytes, but the evidence for RDD is a finding of lymphocytes within the cytoplasm of sinus histiocytes. Inflammatory pseudotumor and RDD have been found in the same patient suggesting a histologic continuum [22].

Treatment

First, it is important to emphasize that treatment is strictly individual. RDD does not usually pose a threat to life-threatening illnesses nor cause any significant organ failure and the prognosis is good despite the damage of the tissue (but worsening with the number of affected nodes) [7]. The decision about treatment is difficult due to the different forms, course and degree of the disease. In some cases, the symptoms resolve over months or years (spontaneous remission in 70–80% of cases) and therefore clinical observation without treatment is often recommended (if possible). In some cases, treatment is important [7–8]. Multiorgan lesions and association with immune dysfunction are poor prognostic indicators and indicate the necessity of treatment. Therapeutic options include treatment of specific symptoms - surgical (lymph nodes, central nervous system lesions, localized skin lesions), pharmacological (steroids, alpha-interferon, thalidomoide, azathioprine) or chemotherapy and radiotherapy. The basic chemotherapeutics to treat RDD include vinblastine, 6-mercaptopurine, methotrexate or cytarabine, clofarabine and cladribine. A classical rule applies here - take the lowest possible dose of the chemotherapeutic agent so as to keep the disease under control while ensuring a good quality of life [4,7]. Radiotherapy is rather used as a second option in the case of the relapse of RDD or impossibility of surgical option or as an additional or palliative treatment. The dose range is not standard and is between 30 and 50 Gy. In the case of increased immunoglobulins, plasmapheresis is another therapeutic option. Furthermore, the symptomatic treatment in general is also important. For more details see recommendations of an international panel of experts who recently published consensus for diagnosis and clinical management of RDD [5].

Case presentation

This case report deals with a young 40-year-old man of Slovak nationality living with his family in the Czech Republic and working in a car factory as a welder. So far, he has not been cured for anything and he has not taken any medication. The family history from the neurological point of view includes his father's epilepsy. He has not smoked for 10 years, however, until then he managed to smoke 30 cigarettes a day.

Since May 2017, he has been observing the loss of smell and taste, without a history of trigger or an injury, supposedly preceded by a celebration with a bigger amount of alcohol with subsequent nausea and elevated temperatures. In addition, in mid-October, he began to observe the impaired vision of the left eye (deterioration of the visual acuity, the glitter feeling and sensation of looking into the sun). He was examined in the eye outpatient department where the reduction of visual acuity and the absolute scotoma both of the left eye was found out.

Then in November he was hospitalized in the Neurological Clinic of the University Hospital of Hradec Králové (UHHK) after the CT of brain, where extensive areas of vasogenic edema were described in both frontal and right temporal lobe (Fig. 1A). During an entry neurological examination, he did not show signs of cerebral infarction, he was only slightly euphoric. No significant pathological values were found in laboratory samples, including blood count, coagulation, sedimentation and basic biochemical examination (glucose, minerals, renal parameters, liver enzymes, CRP (C-reactive protein), protein, TSH (thyroid stimulating hormone)), paraprotein was not proved and normal record was taken during the EEG. Supportive MRI confirmed multifocal opacifying lesions in the locations corresponding to the CT scan (Fig. 1B, 2). Differential diagnosis remained wide, among which the possibility of multiform glioblastoma was considered.

To reduce vasogenic edema corticosteroids have been introduced into the therapy (dexamethasone 24 mg a day) from the second day of hospitalization and then the patient was transferred in a clinically unchanged condition to the Neurosurgery Clinic of the UHHK to complete the open biopsy as the last diagnostic option. According to the neuronavigation examination prior to the procedure, there was a partial regression of the vasogenic edema and the postcontrast opacifying lesions (Fig. 3), which can be attributed to the newly applied corticotherapy, which was gradually reduced to the dosage of 4 mg a day. The open biopsy was done without complications, and the samples were subsequently sent for histological verification, which was concluded after several days as meningeal form of Rosai-Dorfman disease with reactive gliosis in adjacent tissue without evidence of amyloid.

On the basis of haematologic recommendation, CT of the body showed borderline nodes in the retroperitoneum and mild splenomegaly and bone marrow biopsy showed hypocellular trilinear hematopoesis with reactive changes, without significant dysplastic alterations, without convincing tumor structures. From the pathologic point of view, it probably means histiocytic reactive reaction. When the end of hospitalization was approaching, the patient was feeling better, and therefore he was dismissed home in good condition with recommendation of continuing corticotherapy (dexamethasone 4 mg a day).

In January, March, and then in May 2018, the patient was checked with MRI of the brain with a significant regression of the finding (Fig. 5). According to the outpatient reports of the same year, the taste and vision of the left eye were gradually being adjusted. Therefore, in May it was recommended to gradually discontinue the corticotherapy, and the patient was monitored in the follow-up period, which lasted to the beginning of 2020.

That year in February, the patient was examined in outpatient Department of Neurology of the UHHK because of one month lasting difficulties, mainly vomiting, then narrowing and darkening of vision, sleeplessness, neck pain, dizziness, tingling of upper limbs and headache without effect of painkillers. When receiving an entry neurological examination, he did not show any signs of cerebral lesion. On the basis of a rudimentary laboratory examination, there were no significant findings. He was again acutely hospitalized at the same Department of Neurology of the UHHK and then underwent, MRI which confirmed leptomeningeal opacifying infiltrations on the base of cerebellum and temporo-parieto-occipitally on the left side (Fig. 6). Considering the effect of corticosteroids during the first attack of the disease, he was treated with dexamethasone 24 mg a day again. This new progress of the case was discussed during the oncological seminar with neurosurgeons with conclusion that rebiopsy from posterior cranial fossa would be potentially dangerous and could have a low benefit. Afterwards, lumbar puncture was performed. The results of the basic cerebrospinal fluid examination showed that there was only marginal elevation of protein, lactate and leukocytes, otherwise no significant findings (including Borrelias and neurotropic viruses), immunophenotyping of cerebrospinal fluid brought the information of 85% dominance of lymphocytes (88% of T-lymphocytes mainly CD4+ helper ones and 11% of B-lymphocytes) and no findings of pathologic populations of haemopoetic cells. No specific haematologic therapy was indicated. When the end of hospitalization was approaching, the patient was feeling better, and therefore he was dismissed home in good condition. The corticotherapy with dexamethasone remained temporarily, with the dose of 12 mg in the time of dismission, and was gradually discontinued in the next 2 weeks after hospitalization. Then, he continued in haematologic follow-up, underwent MRI of the whole spine and PET/CT of trunk; both of them with no significant findings. According to the last outpatients report in October the same year, the patient was feeling better with no symptoms of the disease. Therefore, from the haematologic point of view, no specific system treatment was recommended with arguments of localized (CNS) disease without generalization and absence of neurological symptoms (with their return, the long-term corticotherapy would be recommended).

Discussion

RDD is a rare disease and its intracranial form even more, worldwide estimated about 5 % of all cases of RDD [5,23], and is found in patients with a mean age of 37.5 years [16,24]. Until 2014, 210 cases were documented and the last 99 of them in the years from 2009 to 2014, which means the incidence of meningeal form of RDD is gradually growing. This is supported by Gaurav et al., who have examined 64 patients during 23 years with incidence of 3 patients per year but in their last 5 years, the incidence has grown to almost 6 patients per year [23]. The reason might be better awareness of this disease, better diagnostic possibilities or factors associated with RDD (increasing incidence of autoimmune diseases, worsening environment). The most frequent structure affected by intracranial form of RDD is dura mater which can imitate meningeal tumor. Therefore, the meningeal form of RDD should be considered in the differential diagnosis of intracranial/intraspinal dural meningiomas [20]. The symptoms of intracranial form of RDD are varied, depending on the localization, just like any intracranial lesion, but mostly associated with headaches, seizures or visual disorder; [5,25] other are, for example, limb weakness, decreased muscle tone, ataxia, tremor, vomiting, dizziness, sensory and hearing impairment, disorientation and many more [5,6,16,23,25,26]. The most frequent therapeutic option of intracranial form of RDD is surgery, which is used not only for the treatment, but also as a diagnostic option. If surgery is not successful or indicated, the radiotherapy is used. Some studies used chemotherapy and as the promising combination came off methotrexate and 6-mercaptopurine. Corticoids are used as a system therapy [24]. We had used them due to vasogenic edema before we even knew the diagnosis. As we presented on the MRI scans, the corticoids caused regression of not only the edema but also the opacifying lesions. We used these findings during the relapse of RDD, so far with a good clinical outcome (the patient has had no MRI check yet).

Conclusion

This case describes a rare haematologic disease with primary manifestation in the CNS. Due to the growing incidence of the intracranial form of RDD, it is also important to raise awareness of this disease generally, not only for neurologists. The differential diagnosis is broad, from incurable glioblastoma multiforme with the prognosis of several moths of survival to the rare RDD itself with a good response to the treatment and a very good prognosis.

Ethical principles

The study is not subject to approval by the ethics committee; the patient has signed an agreement with the diagnostic and treatment process.

Disclosure

Oldřich Medek, Petra Kašparová, Michael Bartoš, Blanka Klímová, Martin Vališ, Tomáš Kupsa, Jan M. Horáček, and Helena Medková declare no disclosures.

The Editorial Board declares that the manu script met the ICMJE “uniform requirements” for biomedical papers.
Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.

Assoc. Prof. PhDr. Blanka Klímová, M.A., PhD
Department of Neurology
Faculty of Medicine
of Charles University
University Hospital
Sokolská 581
500 05 Hradec Králové
Czech Republic
e-mail: blanka.klimova@uhk.cz
Accepted for review: 21. 4. 2021
Accepted for print: 9. 9. 2021

An extended version of the article is available at csnn.eu.