Rosai-Dorfman disease is primarily encountered in adolescents, as more than 80% of cases are diagnosed in patients under 20 years of age, and a small, but significant predilection toward male gender is observed [1] [2]. The clinical presentation is diverse, but the deposition of histiocytes in lymphatic tissues is primarily manifested as massive and painless bilateral cervical lymphadenopathy, which is considered to be the hallmark of the disease [1] [3]. For this reason, the term sinus histiocytosis with massive lymphadenopathy (SHML) is often used as a synonym [1] [3]. Fever, weight loss, night sweats, malaise, and pharyngitis are additional symptoms, while enlargement of other lymph nodes (axillary, mediastinal, inguinal, retroperitoneal) is reported in some cases [4] [5]. Extranodal accumulation of histiocytes was reported in numerous sites, including the genitourinary and gastrointestinal tracts, the lungs, skin, heart, musculoskeletal system, thyroid gland, the orbit and in very rare cases, the central nervous system and the breast [1] [6]. As a result, a myriad of symptoms can be seen depending on the organ or tissue involved - Headaches and seizures, in addition to constitutional symptoms, are reported when the head and neck area is the site of histiocyte proliferation, whereas solitary or multiple skin lesions of various types (macular, papular, nodular, xanthomatous) or a soft tissue mass may be seen on the face, trunk, extremities or genitalia in the case of skin or soft tissue deposition [4].

• Lymphadenopathy

  The disease was complicated by hypereosinophilia and massive retroperitoneal lymphadenopathy. [thedoctorsdoctor.com]

  Most common presentation is with massive painless cervical lymphadenopathy, which in most cases is bilateral. Involvement of other lymph node groups is also common. However, in our patient there was no significant lymphadenopathy. [casereports.in]

  FINAL DIAGNOSIS The histological and immunohistochemical features support Sinus Histiocytosis with Massive Lymphadenopathy, also known as Rosai-Dorfman Disease. [path.upmc.edu]

  Most (95%) patients present with cervical lymphadenopathy; inguinal and axillary lymphadenopathy also are common features, present in 44% and 38% of patients, respectively. [ajnr.org]

  […] disease, anaplastic large cell lymphoma, immunohistochemistry Abstract Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare and benign source of lymphadenopathy first described in 1969. [ejcrim.com]

• Anemia

  Laboratory results at time of presentation included a white blood cell count of 29,000/mm 3 and indications of microcytic anemia. [ajnr.org]

  A poor prognosis correlates with widespread dissemination, involvement of the kidneys, lower respiratory tract, or liver, and immunologic abnormalities or anemia (2). [path.upmc.edu]

  A subset of patients with skin limited disease have associated immune disorders such as lupus, autoimmune hemolytic anemia, and Crohn disease. [ncbi.nlm.nih.gov]

  Laboratory evaluation should follow, and anemia, elevated erythrocyte sedimentation rate and hypergammaglobulinemia are cardinal features of Rosai-Dorfman disease. [symptoma.com]

• Swelling

  Finally, RDD should be included in differential diagnosis of lymphadenopathy and parotid swelling even in very young children. [ncbi.nlm.nih.gov]

  The swellings had gradually increased in size and number, and other swellings had developed in the axillae and groins. Asymptomatic skin lesions had started developing on the face and left thigh since 1 year. [ijdvl.com]

• Pallor

  On examination, she was moderately built and nourished and had mild pallor. The cervical, axillary and inguinal lymph nodes were grossly enlarged, 2-3 cm in size, firm, nontender and non-matted in a bilaterally symmetrical pattern. [ijdvl.com]

  Clinical examination revealed average built, mild pallor along with generalized lymphadenopathy involving right cervical (2 × 1.5 cm, multiple, matted) ( Figure 1 ), right axillary (1 × 1 cm), and right inguinal (2 × 2.5 cm) lymph nodes. [ncbi.nlm.nih.gov]

  In some cases, affected individual may experience nonspecific symptoms that are common to many different conditions including fever, paleness of the skin (pallor), unintended weight loss, a general feeling of ill health (malaise) and a chronically runny [rarediseases.org]

• Short Stature

  Faisalabad histiocytosis mimics Rosai-Dorfman disease: brothers with lymphadenopathy, intrauterine fractures, short stature, and sensorineural deafness. Rossbach HC, Dalence C, Wynn T, Tebbi C. Rossbach HC, et al. [pubmed.ncbi.nlm.nih.gov]

  stature, cardiac anomalies, and scrotal masses are not present in our patient thus making it an unlikely diagnosis. [18] Additionally, biopsies of involved skin in H syndrome demonstrate acanthosis and the infiltrate is composed of mast cells as well [e-ijd.org]

  Inherited conditions predisposing to RDD or RDD-like lesions H syndrome is an autosomal genetic condition characterized by hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, low height (short stature), [doi.org]

• Generalized Lymphadenopathy

  We describe the case of a 50-year-old lady suffering from this disease who presented with generalized lymphadenopathy and a left sided chest wall lump. [ncbi.nlm.nih.gov]

  RDD typically presents insidiously with generalized lymphadenopathy and a polymorphic histiocytic infiltration of the lymph node sinuses. [wjso.biomedcentral.com]

  Acknowledgment The authors would like to thank General Medicine Department, Siddhartha Medical College, Vijayawada. References 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. [jdrntruhs.org]

• Chest Pain

  Here, we report a case with extra nodal RDD in whichcardiac involvement was detected.Methods: A- 62-years-old male patient was referred to cardiologyclinic with the complaints of atypical chest pain and dyspnea. [dokumen.tips]

  pain, although nearly 20% of adults with lung involvement have no symptoms.[ 9, 10 ] Chest pain may indicate a spontaneous pneumothorax (10%–20% of adult pulmonary LCH cases). [alda.hassanflores.com]

• Papule

  A 25-year-old woman presented with multiple erythematous and yellowish papules on the forehead, cheeks, chin and thigh. She had massive generalized, firm, non-tender and non-matted lymphadenopathy and mild hepatomegaly. Her hemogram was normal. [ijdvl.com]

  [ 1 ] Lower back 45 M Clusters of pinkish papules S-100+ Yes 26 months; no recurrence CD68+ 15 Kong et al, 2007 [ 1 ] Upper left arm 52 F Red to brownish plaque with scattered papules and nodules S-100+ Yes 8 months, no recurrence CD68+ CD1a+ 16 Kong [wjso.biomedcentral.com]

  The patient presented with a large pigmented plaque on her left leg, and sparse erythematous papules on her face and arms. A complete clinical response was achieved with thalidomide, followed by recurrence at the initial site one year later. [ncbi.nlm.nih.gov]

  The lesion had originated as a small, tender, erythematous papule and had since grown into a large confluent plaque with satellite papules. She claimed that the lesion was increasing in size, and this was accompanied by intense itching and fever. [jamanetwork.com]

• Night Sweats

  Fever, weight loss, night sweats, malaise, and pharyngitis are additional symptoms, while enlargement of other lymph nodes (axillary, mediastinal, inguinal, retroperitoneal) is reported in some cases. [symptoma.com]

  A vast majority of patients (~80%) present with painless massive cervical lymphadenopathy, with associated fever, malaise, weight loss and night-sweats 14. [radiopaedia.org]

  Additional findings may include fever, malaise, epistaxis, night sweats, weight loss, leukocytosis, elevated erythrocyte sedimentation rate and hypergammaglobulinemia. [orpha.net]

  It is more common during the first 10 years of life, is equally common in persons of African and Caucasian descent, and has a slight male predilection. 1 Clinically, adenopathy progresses over 3 to 9 months, and fever, night sweats, and weight loss may [consultant360.com]

• Skin Lesion

  The skin lesions of CRD in the presenting case regressed after 2 months of dapsone treatment alone. [jamanetwork.com]

  lesions of various types (macular, papular, nodular, xanthomatous) or a soft tissue mass may be seen on the face, trunk, extremities or genitalia in the case of skin or soft tissue deposition. [symptoma.com]

  To identify histopathologic and immunohistochemical findings in skin lesions that permit diagnosis. [e-ijd.org]

  Asymptomatic skin lesions had started developing on the face and left thigh since 1 year. On examination, she was moderately built and nourished and had mild pallor. [ijdvl.com]

  The skin lesion was excised under general anesthesia. In the Pathology Department, we received a small, partially skin covered, well circumscribed nodule, measuring 1 cm in diameter. Cut section was grey-white and firm in consistency. [ijpmonline.org]

• Cutaneous Manifestation

  In 1978, Thawerani et al emphasized the cutaneous manifestations Rosai-Dorfman syndrome. [ijdvl.com]

  Huang HY, Yang CL, Chen WJ (1998) Rosai-Dorfman disease with primary cutaneous manifestations—a case report. Ann Acad Med Singapore 27:589–593 PubMed Google Scholar 15. [springerlink.com]

  "Rosai-Dorfman disease presenting with extensive cutaneous manifestation - case report.". An Bras Dermatol 88 (2): 256-9. doi : 10.1590/S0365-05962013000200014. [librepathology.org]

  The cutaneous manifestations of sinus histiocytes with massive lymphadenopathy. Arch Dermatol 1978;114:191-7. [ PUBMED ] 8. Chu P, LeBoit PE. [jdrntruhs.org]

• Skin Papule

  A reddish rash-like inflammation of the skin (erythema), small solid elevations on the skin (papules), or knots visible under the skin (nodules) may be present. Skin lesions may occur anywhere on the body, but most often affect the head and neck. [rarediseases.org]

  papules or nodules and does not present with the usual myriad of symptoms of classical RDD. [e-ijd.org]

• Confusion

  The variable amounts of cellular reactive fibrosis displayed in storiform pattern in cutaneous lesions of RDD may be confused with a dermatofibroma. Fibrosis and foamy histiocytes may be especially prominent in older lesions. [ijpmonline.org]

  There are histiocytes engulphing nuclear debris (bean bag cells) which should not be confused with emperipolesis. The lymphocytes demonstrate nuclear atypia and can be seen to characteristically rim the adipocytes. [dermnetnz.org]

  Finally, metastatic melanoma may be confused with SHML; however, melanoma stains positively for HMB45 and MelanA in addition to S-100 (4). [path.upmc.edu]

  Confusion d. Muscle twitching What are the side effects of methotrexate? Side effects include: a. Mouth sores/swollen, tender gums b. Nausea/vomiting/diarrhea/decreased appetite c. Low blood counts d. Dizziness/drowsiness e. [histiouk.org]

  Instrumental exams might confuse RDD with other malignancies. RDD is a rare entity, which might be misdiagnosed using PET-CT due to its similarities with malignant tumors. [chirurgiadelfegato.it]

Although signs and symptoms may be numerous and non-specific, the presence of bilateral cervical lymphadenopathy must raise clinical suspicion. However, key findings can only be obtained after a meticulous physical examination and a thorough patient history, which are key step during workup. Laboratory evaluation should follow, and anemia, elevated erythrocyte sedimentation rate and hypergammaglobulinemia are cardinal features of Rosai-Dorfman disease [3] [4] [5]. Because the differential diagnosis involves numerous conditions of infectious and neoplastic (both lymphoproliferative and metastatic forms) origin or disorders of similar pathophysiological mechanisms (such as Langerhans cell histiocytosis), imaging studies are required in order to assess additional organ involvement. Computed tomography (CT) and magnetic resonance imaging (MRI) are recommended procedures, but depending on signs and symptoms, additional studies may be required (ultrasonography, mammography, scintigraphy, echocardiography, etc). To confirm Rosai-Dorfman disease, a histopathological examination is necessary [4]. A dense infiltrate of large histiocytes containing large nuclei, small nucleoli, and a pink cytoplasm, as well as scattered lymphoid cells (lymphocytes and neutrophils) are main characteristics of this condition [5]. The most important distinguishing feature, however, is emperipolesis, defined as the presence of intact lymphoid cells within histiocytes, and is considered as a pathognomonic feature of Rosai-Dorfman disease [5]. In addition, positive S-100 and CD68 , together with negative CD1a, are key findings on immunohistochemistry testing [3] [5].

• Normocytic Anemia

  Laboratory testing usually shows leukocytosis, polyclonal hypergammaglobulinemia, hypochromic or normocytic anemia, and elevated erythrocyte sedimentation rate. The disorder commonly resolves without treatment. [msdmanuals.com]

  Upwards of 80% of patients demonstrate polyclonal hypergammaglobulinemia and as many as 65% have a hypochromic or normochromic normocytic anemia [ 16 ]. [wjso.biomedcentral.com]

  Two patients presented with mild leukocytosis and 2 presented with mild leukopenia (median white blood cell count, 7.2 × 10 3 / μ l; range, 2.4–18.3 × 10 3 / μ l; reference range, 4–11 × 10 3 / μ l), 6 patients had mild normocytic anemia (median hemoglobin [nature.com]

• Foam Cell

  Foam cell with palely eosinophilic bubbly cytoplasm abundantly granular with open vesicular nuclei with prominent nucleoli were also observed ( Fig. 2 e–i). [reumatologiaclinica.org]

• Leukocytosis

  Leukocytosis and elevated ESR have been reported in most cases. Normocytic/normochromic and autoimmune hemolytic anemia with elevated serum ferritin has been reported in some cases. [casereports.in]

  Is rare as isolated cutaneous presentation and appears with hyperpigmented or erythematous papules, nodules or plaques. 1 Affects lymph nodes as well as extra-nodal areas as a systemic disease with fever, leukocytosis, elevated erythrocyte sedimentation [reumatologiaclinica.org]

  Accompanying features are fever, leukocytosis, and weight loss. [symptoma.com]

  Rosai-Dorfman disease was commonly characterized as massive, painless, bilateral, symmetric cervical lymphadenopathy, with fever, leukocytosis, and elevated sedimentation rate. [ncbi.nlm.nih.gov]

Because it is so rare, no large studies have been done, and there is no established treatment. [consultant360.com]

Primary treatment with surgical excision and radiation has been attempted but has not proved to be of consistent value. [ajnr.org]

No specific treatment has been advocated for this essentially self-limiting disease, which has a good prognosis [7]. Surgical treatment of resectable lesions gives complete remission. [casereports.in]

Pre- and post-treatment magnetic resonance images. [pagepress.org]

This therapeutic regimen generally delivers a good prognosis. [ncbi.nlm.nih.gov]

Although limited in size, this series suggests the prognosis of patients with RDD and intrathoracic manifestations is relatively good. [mayoclinic.pure.elsevier.com]

Treatment and prognosis Rosai-Dorfman disease usually follows a benign and self-limiting course with treatment largely targeted at controlling local manifestations (surgical intervention) 6. [radiopaedia.org]

Abstract quote Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, is a very rare disorder of unknown etiology. [thedoctorsdoctor.com]

The optimal treatment remains controversial, and more efforts should be focused on the investigation of etiology and adjuvant therapy for relapsing cases or subresected lesions. [ncbi.nlm.nih.gov]

To help improve awareness of Rosai-Dorfman spinal disease, we review the literature and discuss the epidemiology, clinical presentation, imaging features, and treatment considerations for this condition. [ncbi.nlm.nih.gov]

Epidemiology and Demographics The incidence of this disease is It is a disease of the childhood. Natural History, Complications and Prognosis The symptoms of this disease vary with the site of accumulation similar to other regional tumors. [wikidoc.org]

* Department of Dermatology, Boston University School of Medicine, Boston, MA; † Department of Hematology and Oncology, Boston Medical Center, Boston, MA; ‡ Massachusetts Area Veterans Epidemiology Research and Information Center (MAVERIC), VA Cooperative [journals.lww.com]

The epidemiology of extranodal RDD manifesting in epibulbar masses has evolved over the years. Currently, there are 20 reported cases [ 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ]. [karger.com]

The epidemiologic, laboratory and histologic findings are similar among patients with nodal and extranodal involvement suggesting a common biologic basis. [ispub.com]

Because the differential diagnosis involves numerous conditions of infectious and neoplastic (both lymphoproliferative and metastatic forms) origin or disorders of similar pathophysiological mechanisms (such as Langerhans cell histiocytosis), imaging [symptoma.com]

Pathophysiology Lymphadenopathy of the neck is the most common place of histiocyte accumulation, although accumulation outside of lymph nodes may occur, as well. [wikidoc.org]

The underlying pathophysiology of this overlap and the clinical significance with respect to treatment and prognosis is not yet clear. [err.ersjournals.com]

Although many patients experience spontaneously regressing courses, some, such as our patients, will have disease present in a more extensive form requiring treatment, in some cases to prevent functional loss. [ajnr.org]

NCI_CTEP-SDC (Cancer Therapy Evaluation Program - Simple Disease Classification) 2015AB NCI_CareLex (Content Archive Resource Exchange Lexicon) 2015AB NCI_DCP (NCI Division of Cancer Prevention Program) 2015AB NCI_DICOM (Digital Imaging Communications [doctor.am]

She refused superficial radiation treatment and the large size of the lesion prevented the tumor from being simply excised. A safe and effective alternative treatment was needed. [jamanetwork.com]

Although those cases do not assist with the issue of the proper dose–fractionation schedule for rdd lesions, they do provide some evidence that, in selected cases, disease recurrence can be prevented or delayed with the use of either primary or postoperative [current-oncology.com]

1. Sendrasoa FA, Ranaivo IM, Raharolahy O, et al. Rosai-Dorfman Disease Involving Multiple Organs: An Unusual Case with Poor Prognosis. Case Rep Med. 2016;2016:3920516.
2. Ribeiro BN de F, Marchiori E. Rosai-Dorfman disease affecting the nasal cavities and paranasal sinuses. Radiologia Brasileira. 2016;49(4):275-276.
3. Symss NP, Cugati G, Vasudevan MC, Ramamurthi R, Pande A. Intracranial Rosai Dorfman Disease: report of three cases and literature review. Asian J Neurosurg. 2010;5(2):19-30.
4. Najafi-Sani M, Saneian H, Mahjoub F. Rosai-Dorfman Disease with nodal and extranodal involvements: A case report. J Res Med Sci. 2011;16(9):1251-1256.
5. El Majdoub A, El Houari A, Chbani L, El Fatemi H, Khallouk A, Farih MH. Isolated localization of Rosai Dorfman disease as renal mass: a case report and review of literature. Pan Afr Med J. 2016;24:64.
6. Zhou Q, Ansari U, Keshav N, Davis F, Cundiff M. Extranodal manifestation of Rosai-Dorfman disease in the breast tissue. Radiol Case Rep. 2016;11(3):125-128.