key: cord-0861127-u21o7984
authors: Giri, Kalpana; Baral, Ashok; Tiwari, Niva; Sharma, Krishna Sagar
title: Rosai‐Dorfman disease in 6‐year‐old child: Presentation, diagnosis, and treatment
date: 2021-09-21
journal: Clin Case Rep
DOI: 10.1002/ccr3.4795
sha: 8d5ca12ce3715e56b45544d2071354e420e55205
doc_id: 861127
cord_uid: u21o7984

Rosai‐Dorfman disease is referred to as sinus histiocytosis massive lymphadenopathy. We are reporting a rare case of Rosai‐Dorfman disease, a case of 6‐year‐old boy with a history of multiple painless submandibular and cervical lymphadenopathy.

Rosai-Dorfman disease (RDD) is referred to as sinus histiocytosis massive lymphadenopathy (SHML) of unknown origin. We are reporting a rare case of Rosai-Dorfman disease, a case of 6-year-old boy with a history of multiple painless bilateral submandibular and cervical lymphadenopathy.

Rosai-Dorfman disease known as sinus histiocytosis with massive lymphadenopathy (SHML) is a benign systemic histio proliferative disease presented clinically with bilateral painless cervical lymphadenopathy, fever, and have leukocytosis on blood examination. Histopathological examination shows pericapsular fibrosis with dilated sinuses, large histiocytes with intact phagocytized lymphocytes heavily infiltrated with large histiocytes, lymphocytes, and plasma cells in the background. 1 It is common in children and young adult. 2 We are reporting a case of 6-year-old boy with a history of multiple painless bilateral submandibular and cervical lymphadenopathy. This is one of the rare cases diagnosed in our hospital. The diagnosis of Lymphoma was suspected, and the patient underwent lymph node biopsy. Histopathological and immunohistochemistry confirmed the diagnosis of RDD.

It is one of the differentials of cervical lymphadenopathy so clinicians and pathologists must be aware of it. RDD is an idiopathic disorder, but its occurrence has frequently been observed after infection, possible viral etiology, such as Epstein-Barr virus (EBV), human herpes 6, parvovirus B19 (HHV-B19), and polyomavirus, has been suggested by several authors, supported immunohistochemistry, PCR, and in place hybridization studies. 3 About 43 percentage of RDD have extranodal involvement mostly in the head and neck with similar morphological features as nodal RDD. 4 They can also be found in skin soft tissues, upper airways, bones, and brain. S-100 protein can be demonstrated in diagnostic immunohistochemistry in sinus histiocytes. 5 It is mostly a self-limiting disease; however, surgical resection remains the mainstay of treatment for symptomatic disease. Several studies have shown that the combination of cytotoxic agents and prednisolone also shown to be effective for treatment.

A 6-year-old boy, first presented to the otorhinolaryngology clinic of a peripheral hospital 6 months back with complaints of bilateral neck swelling for 1 month. Histological examination of a biopsy showed lymphoproliferative disease. He received Prednisolone 30 mg for 5 months, but the lesion did not respond to Prednisolone then referred to our cancer hospital. At presentation general condition is fair; fever, night sweats, weight loss, cough, and other general symptoms were absent. Physical examination revealed enlarged bilateral multiple cervical and submandibular lymph nodes, difficulty in neck movement due to swelling. Neck swelling on palpation: firm, mobile, non-tender with the largest size measuring 8*10 cm (Figures 1-3) .

On systemic examination: No hepatosplenomegaly; cardiovascular, respiratory, and nervous systems were found normal. Family history was unremarkable. Laboratory investigation: hemoglobin 9.1% with total leucocyte count 17,700/mm 3 , platelet count: 5,48,000/mm 3 . Peripheral Blood smear (PBS) revealed increased on smear with neutrophils: 87%, lymphocytes: 10%, eosinophils: 2%, monocytes: 2%. Biochemistry reports sodium; 129.18 mmol/L, magnesium; 1.7 mg/dl, calcium; 7.9 mg/dl, SGPT/ALT; 5 U/L. Random blood glucose (RBS), urea, creatinine, lactate dehydrogenase, alkaline phosphatase, electrocardiography, bleeding time, clotting time, prothrombin time (PT)/international normalized ratio (INR), Human Immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV), Polymerase chain reaction (RT-PCR) for Covid-19 were in the normal range. Ultrasound of neck revealed a few enlarged bilateral cervical lymph nodes noted at all levels (anterior, mid, and posterior region), the largest one measuring about 30 * 20 mm in right and measuring about 46 * 26 mm in left.

Plain and contrast-enhanced helical scan of neck, chest, abdomen, and pelvis revealed multiple bilateral cervical at level IB, II, III, IV, V, and VI, bilateral supraclavicular, mediastinal, bilateral axillary, and retroperitoneal lymphadenopathies (Figures 4-6) .

A lymph node biopsy (excised from right cervical) was done. Histopathology report revealed lymph node with follicular hyperplasia and distension of sinuses with the proliferation of foamy histiocytes engulfing lymphocytes and red blood cells (Figure 7) . Atypical cells not seen. On Immunohistochemistry, these cells displayed a positive reaction to CD68 and S-100 protein, whereas the reaction to CD1a was negative. These findings confirmed the diagnosis of Rosai-Dorfman Disease. The patient was treated with the first cycle of chemotherapy. He received 1st cycle of (Injection vinblastine 4 mg I/V) and got discharged with oral prednisolone-30 mg for 5 days in divided doses. On phone follow-up, the patient and her parents mentioned that he is doing well the lymph node size is decreasing.

Rosai-Dorfman disease is a rare, benign disorder proliferative histiocytic disorder recognized clinically and pathologically in 1969 through a publication by Rosai and Dorfman. 1 The etiology of RDD is unknown. Over the years, there are many theories attempting to elucidate RDD's pathogenesis, but each of them has led to conflicting results. Researchers have indicated infectious agents have potential causes of RDD, like human herpesvirus-6 (HHV-6), 6,7 human herpesvirus-8 (HHV-8), parvovirus B19, Epstein-Barr virus (EBV), 7 cytomegalovirus (CMV), varicella-zoster virus (VZV), Brucella, and Klebsiella; however, there is no conclusive evidence to verify this theory. It had been observed that primarily infected lymphocytes induce a secondary histiocytic reaction that eventually causes the characteristic microscopic image of RDD, suggested by the authors in one of the articles. 8 Ju et al. reported a case of RDD in a 26-year-old man with cervical and mediastinal lymphadenopathy with pleural effusion in 2009. 9 Studies done by Atin Agarwal et al. in India includes seven cases (five nodal and two extranodal) of SHML over a 5-year period whose slides and blocks were reviewed, which showed one of them developed histiocytic sarcoma. 10 Zhu et al. include 13 cases sample, 10 (77%) were purely extranodal RDD, 2 (15%) were both nodal and extranodal, and 1 (8%) was purely nodal. The locations of the 10 purely extranodal RDD lesions included the central nervous system, nasal cavity, and paranasal sinuses (30%), and cutis (10%). 11 F I G U R E 1 Multiple massive, firm, non-tender, mobile lymph nodes bilaterally largest measuring 8*10 cm in the cervical and sub mandibular region with scars of biopsy Rosai-Dorfman disease is significantly more common among Caucasians and blacks than among Asians. 12 It is most commonly seen in children and young adults. 13 RDD in children may mimic 

Histopathology examination showing lymph node with follicular hyperplasia and distension of sinuses with the proliferation of foamy histiocytes engulfing lymphocytes and red blood cells malignancy because of rapidly progressive lymphadenopathy as presentation. 14 The patient mostly presents with bilateral painless cervical lymphadenopathy (87%). Initially, lymph nodes are mobile and discrete but later become large, multinodular, and adherent. The axillary (23.7%), inguinal (25.7%), and mediastinal (14.5%) regions may be affected, though not as severely as the cervical region. 15 In this case, our patient also presented with painless cervical lymphadenopathy. Extranodal tissue involvement is recorded in 43% of RDD patients, especially of the skin, soft tissues, brain, upper airway, bones, urogenital system, lower airway, and oral cavity. 4 Fever is one of the clinical manifestations of 30% of RDD patients 16 but in our case fever was absent. Some patients present with immunological abnormalities including leukocytosis, altered T4 lymphocytes, and T8 lymphocytes ratios (T4/T8), decreased lymphocyte mitogenic responses, and hypergammaglobulinemia. In these cases, extranodal involvement is present in about half of the cases. 17 RDD is frequently associated with a high erythrocyte sedimentation rate (ESR) and polyclonal hypergammaglobulinemia (up to 90% of cases), anemia, and neutrophilic leukocytosis. 18 Our patient presented with cervical lymphadenopathy, neutrophilic leukocytosis (87%), and anemia (Hemoglobin = 9.1 mg/dl).

The origin, pathogenesis of the disease, and histogenesis of the proliferating cell are still unknown or uncertain. The cell of Rosai-Dorfman disease can still not be classified as a Langerhans type dendritic cell or as a non-Langerhans phagocytic histiocyte. 17 Some authors have found some viruses like human herpesvirus-6 (HHV-6), and Epstein-Barr virus (EBV), and some bacterial infection klebsiella to be associated with its etiopathogenesis. [19] [20] [21] But the cause is still not proved. 17 The diagnosis of RDD is based on the physical examination, clinical history, and confirmed by histopathological examination. Specimens could also be obtained by open surgical biopsy or fine-needle aspiration. Fine needle aspiration is considered a sensitive and reliable diagnostic method. The excised lymph nodes are often grayish with capsular fibrosis. In patients with long-standing lymphadenopathy, the architecture of the lymph node is disrupted where lymph node sinusoids are markedly expanded due to lymphatic stasis and show a mixed cell population, including plasmocytes, lymphocytes, and histiocytes. In RDD, one of the important histological finding is histiocytes with a variable number of phagocytosed cells, usually lymphocytes, plasmocytes, or erythrocytes. The lymphocytes, which remain viable inside the vacuoles, give rise to a phenomenon known as lymphophagocytosis or emperipolesis, known as the presence of intact lymphocytes inside other cells, in this case, histiocytes. 22 The differential diagnosis of RDD related to clinical and histological features can include reactive lymph node hyperplasia, infectious lymphadenitis, Langerhans cell histiocytosis, non-Hodgkin's lymphoma, and metastatic carcinoma. 23 Because of its self-limiting nature as well as less incident rate, no standard treatment protocol has been made for RDD. A review of the literature revealed that 50% of patients with RDD require no treatment and that 82% of untreated patients experience spontaneous and complete disease regression. 21 Some reports showed disease control in children without therapy. 24 In such a case, after careful analysis of the biopsied specimen, a conservative approach was adopted with progressive reduction of the lymphadenopathy. Pulsoni et al. 21 reviewed case reports of 80 patients who received various modes of treatment. Systemic corticosteroids are usually helpful in decreasing nodal size and symptoms; however, they can be quite immunosuppressive and RDD lesions can recur after a short period of interruption. 21 Oka et al 25 . reported an effective prolonged course of low-dose prednisolone in a case of RDD with skin and lymph node involvement with respiratory obstruction, its role cannot be generalized. There are not any specific treatment modalities. Corticosteroids, chemotherapy, antibiotic therapy, radiation therapy, and surgical treatment are found to be used. 26 In our patients who had clinical and histopathologic features classic for SHML have received chemotherapy and prednisolone therapy and the disease state has been stable for several months.

This is the case of Rosai-Dorfman disease that involves both submandibular and cervical lymph nodes in a child, without extranodal localization. Clinically presents with painless submandibular and cervical lymphadenopathy with neutrophilic leukocytosis. Histology shows lymph nodes with follicular hyperplasia and distension of sinuses with the proliferation of foamy histiocytes engulfing lymphocytes and red blood cells. Immunohistochemistry shows histiocytes positive for CD68 and S-100 protein, and negative for CD1a. Most cases with this disease will not require treatment. For those who require treatment, chemotherapy, steroid, as in this case should be given. Also, radiation therapy, surgery have been required for those who don't respond to medical therapy. RDD should be included in the differential diagnosis of submandibular and cervical lymphadenopathy even in very young children.

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