Rosai- Dorfman Disease (Sinus histiocytosis with massive lymphadenopathy) –A Case Report by Asanka De silva

Abstract
Rosai-Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy is a rare disease of unknown aetiology. First described in 1969 with painless cervical lymph node enlargement in association with fever, weight loss and sweating. 43% of cases were reported extra nodally that commonly involving skin, upper airway, and salivary glands12. RDD is usually seen in young patients. Cutaneous lesions are the common form of extranodal diseases, but cases of purely cutaneous lesions without nodal or other extranodal involvement are rare, Proliferation of large pale or foamy histiocytes exhibiting enlarged vesicular nuclei, prominent nucleoli, and distinctive lymphophagocytosis or emperipolesis is the basis of the diagnosis. S-100 protein immunophenotype is useful in confirming the disease entity.
This case report is about a 52 yrs old male patient presented with asymptomatic diffuse swelling on left side pre auricular area diagnosed as Rosai-Dorfman disease after histopathological analysis of the excision biopsy. Currently on follow up after 3rd month post operatively.
Key words: emperipolesis, Rosai–Dorfman disease, sinus histiocytosis with massive lymphadenopathy, nodal, head and neck.

Introduction
Rosai-Dorfman disease (RDD) is a benign systemic proliferative disorder of histiocytes resembling the sinus histiocytes of lymph nodes. The typical clinical features of this disease include bilateral painless lymphadenopathy, fever, and polycolonal hyperglobulinaemia. The condition with the head and neck involvement reported in 22% of cases, most commonly the nasal cavity followed by the parotid gland 10. Extranodal involvement in 43% (500 pt’s) of cases, and cutaneous lesions are the most common form of extranodal diseases. The disease is not confined to a particular race or geographical area, although African Negroes are more commonly involved than whites9. Purely cutaneous RDD occur rarely, particularly among Orientals10. Nodal lesions are classified as an inflammatory/hyperplasic disorder which usually undergoes spontaneous regression; extranodal lesion natural history is associated with indolent growth and recurrences along years or decades. It is often confused with lymphoma.
RDD First described in 1969 with painless cervical lymph node enlargement in association with fever, weight loss and sweating that commonly affects children and adolescents. The most common sites affected are the soft tissues of the head and neck and the paranasal sinuses and nasal cavity 10-4.

Case report
A 52 year old male presented to the dental institute Colombo (DIC) with an asymptomatic swelling on lower left side of the cheek for 2 months duration (first noted in November 2010). This lesion had a sudden onset and the size of the lesion gradually increased with time. He first got treatment from general hospital Mathra
where FNAC was done. Microscopically FNAC smear reveal mixed lymphoid cells and many macrophages with engulfed debris and, no oncocytic cells or atypical cells were seen. The report concluded giving differential diagnosis as reactive lymph node and Warthin’s tumour. Then he attended to Dental Institute Colombo for his convenience. On examination firm, non tender swelling apprx.3×4 cm with demarcated margins on palpation was noted on the left side angle of the mandiblular region extending to sub mandibular region.[figure 1] He had history of leptospirosis 5years back and no relevant family history.
Following investigations were done.WBC/DC and blood picture were normal, ESR was slightly elevated (24mm/h), FNAC concluded as inflammatory lesion and suggested histology, Ultra sound scan left side neck suggested Warthin’s tumour and MRI suggested biopsy. There were no radiological abnormalities. Differential diagnosis at surgery was tuberculosis or lymphoma. The lesion was excised including level one lymph nodes and sent for histopathological examination on 27/02/2011. Mantoux test was done later and the result was negative.
Figure 4- Immunoreactivity for S-100
Macroscopically lesions presented as soft nodule and a lymph node.
Microscopic examination of the lymph node [Figure 3] and the lesion revealed partial effacement of architecture with marked capsular fibrosis and sinus histiocytosis. Emperipolesis of lymphocytes and plasma cells is marked immunehistochemically histiocytes showed nuclear and cytoplasmic positivity for S-100 protein [figure 4]. The histopathological examination confirmed the diagnosis Rosai- Dorfman Disease
After the surgery patient was on antibiotics [IV augmentin 1.2g tds] to prevent infection and analgesics on normal regimes. Patient is currently on review appointments without any complaints.
Figure 3 – Histiocyte cells (H&E, ×40)


Discussion
Rosai-Dorfman disease (RDD) or Sinus histiocytosis with massive lymphadenopathy is a rare benign systemic proliferative disorder of unknown aetiology. RDD belongs to broad family of disorders known as lympho reticular disorders which consist of 1.Reactive changes caused by infection and inflammation 2.Autoimmune disorders3.Immunosupression and 4.Neoplasia. Reactive hyperplasia is one of the disease sub types that belong to Reactive disorders of lymph nodes which consist of following categories 1.Follicular hyperplasia – in a predominantly humoral response there is a hyperplasia of the cortical follicles manly composed of B lymphocytes. With development of B cell germinal centres. 2.Parafollicular/ paracoticle hyperplasia - in a predominantly cell mediated response there is a hyperplasia of the paracortical follicles manly composed of T lymphocytes. 3. Sinus hyperplasia/ sinus histiocytosis -Certain stimuli evoke intense phagocytic activity leading to dilatation of subacapsular and medullary sinuses with increased numbers and activity of macrophages and phagocytic lining cells. This reaction is seen in nodes draining tissues from which endogenous particulate matters such as lipid is released. e.g. Necrotic tumour
It is characterised by overproduction of histiocytes or tissue macrophages. This condition was first described by Robb-Smith in children and was termed as giant cell sinus reticulosis in 19479. Sinus histiocytosis with massive lymphadenopathy (SHML) has been recognized as a distinct clinicopathological entity, though first given this name by Rosai and Dorfman in 1969. Incidences very rare, probably less than 1000 cases reported in the literature. The disease is not confined to a particular race or geographical area, although African Negroes are more commonly involved than whites9, 17. Although RDD may occur in any age group, it is most frequently seen in children and young adults14. More than two thirds of registry patients are younger than 10 years. Patients presenting with isolated intracranial disease tend to be older4. The disease is more common in males16 ranging from 1.4:1 to 3:18, 17. Although there is no evidence on aetiology but viruses like Herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV) have been suggested as potential causative agents6. The natural history is that of a regression and resurgence followed eventually by complete resolution.
The clinical picture of RDD is hardly distinguishable from malignant lymphomas which histopathology usually comes as a surprise9. Head and neck involvement has been reported in 22% of cases; most commonly the nasal cavity followed by the parotid gland14, the paranasal sinuses, the nasopharynx, submandibular glands,the larynx, the temporal bone, the intratemporal fossa, the pterygoid fossa, the meninges and the orbit are the other possible sites.Because of gradual awareness of this disease entity, more and more extranodal cases with or without nodal involvement had been documented. To date, extranodal Rosai-Dorfman diseases are still on the rise and accounted for approximately 43% of 600 registry cases, which manifested at least one site of extranodal involvement12.
Clinical Features in most typical forms are painless, bilateral, lymph node enlargement in neck associated with fever, leukocytosis, elevated erythrocyte sedimentation rate in 88.5% of cases, polyclonal hypergammaglobulinaemia. Autoimmune hemolysis can also occur. Most common sites involving are eyes and ocular adnexa (especially orbit), head and neck region, upper respiratory tract, skin and subcutaneous tissues, skeletal system and central nervous system. Other sites are gastrointestinal tract, salivary glands, genitourinary tract, thyroid, breast and uterine cervix.
Table-1
There are different clinical presentations in RDD in head and neck region that reported as Neck mass, facial swelling, Eye swelling, facial pain, Headache and Ataxia, difficulty walking and falls. The differential diagnosis of extranodal SHML may be a challenge15. Comparison of classical clinical case with this case done in table- 1Imaging (CT and magnetic resonance imaging) may be used to assess disease extension. If there is cervical lymph node enlargement, FNAB or lymph node biopsies may be useful for the diagnosis11.The final diagnosis of RDD usually made on characteristic histopathological and cytological features. La Barge et al presented a case series of 13 patients with RDD in head and neck region in 2008 that was reported within 1997–20075. Table 3 gives the summery.
Classical cases of RDD

This case
Clinical features



painless, bilateral, lymph node enlargement
Painless Unilateral lymph node enlargement

Fever
Fever absent

leukocytosis
No leukocytosis

Elevation in ESR
ESR slight elevation

Autoimmune haemolysis
Autoimmune haemolysis absent
Classical histopathology

In this case

Emperipolesis
Emperipolesis marked

Moderately abundant plasma cells and lymphocytes
Moderately abundant plasma cells and lymphocytes

Effacement of involved organ architecture
Partial effacement of lymph node architecture

Positivity for CD68, alpha -1 antitrypsin,s-100, cathepsin E
Positivity being checked for S-100 and positive results gained.
Deferential diagnosis
From Rosai-Dorfman disease
Hodgkin’s lymphoma
Atypical monocytes, Reed-Sternberg cells +
Langerhans’ cell histiocytosis
Emperipolesis absent, Birbeck granules identified by electron microscopy
Inflammatory pseudotumor
Emperipolesis absent, positivity for S-100 protein rare
Malignant histiocytosis and lymphoma with feature of malignant histiocytosis
Atypia, cellular pleomorphism
Hemophagocytic syndrome associated with T-cell lymphoma and/or viral infection
Lymphomatous infiltrate, lobular panniculitis, negativity for S-100 protein
Eruptive xanthoma
Emperipolesis and plasma cells absent
Generalized eruptive histiocytoma

Juvenile xanthogranuloma

Inflammatory malignant Žfibrous histiocytoma
Atypia, cellular pleomorphism
Lepromatous leprosy
Poorly defined infiltrate, plasma cells rare, positivity for organisms on Fite stain
Table-2

The cells have histochemical and phenotypic features of macrophages. Large amounts of esterases and acid phosphatase are contained by the cells. Show positivity for CD 68 and alpha-1 antitrypsin. They also exhibit some of the phenotypic features of dendritic cells such as S100, cathepsin E, fascin and at times CD 1a.6, 71, 8, 13. Skin biopsy non-specific unless emperipolesis is present but lymph node pathology is characteristic. emperipolesis is the presence of an intact cell within the cytoplasm of another cell.
The characteristic histopathological feature of RDD is the proliferation of distinctive histiocytic cells that demonstrate lymphophagocytosis in the background a mixed inflammatory infiltrate consisting of moderately abundant plasma cells and lymphocytes. As a result effacement of involved organ architecture leading to fibrous band formation can be noted19. No Birbeck granules. Birbeck granules are a characteristic microscopic finding in Langerhans cell histiocytosis (Histiocytosis X), which present as shaped or "tennis-racket" cytoplasmic organelles
Age
Sex
Clinical presentation
Location of the disease involvament
2.5
M
Neck masses, autoimmune haemolytic Anaemia
Nodal
5
F
Neck masses
Nodal
38
M
Neck mass
Nodal
30
F
Neck mass, elevated ESR
Nodal and extranodal
33
M
Neck mass, facial swelling
Nodal and extranodal
56
M
Neck masses
Nodal and extranodal
75
M
Left parotid and left neck mass
Nodal and extranodal
12
F
Right eye swelling
Nodal and extranodal
51
M
Left-sided headaches
Extranodal without lymphadenopathy
68
M
Difficulty walking, ataxia, falls
Extranodal without lymphadenopathy
20
F
Facial pain
Extranodal without lymphadenopathy
22
F
Right cheek mass, sinus disease,
no palpable lymph enlargement
Extranodal without lymphadenopathy
19
F
Facial swelling, sinus disease
Extranodal without lymphadenopathy
Table- 3
with a central linear density and a striated appearance.
The differential diagnosis is made with lymphoreticular malignancies such as lymphomas, Hodgkin's disease, malignant histiocytosis and monocytic leukaemia, all of which have similar histopathological features. Atypias in cytology and the aggressive clinical course establish the diagnosis in most cases. Other histiocytoses, such as rhinoscleromas,
Wegener's granulomatosis, may also be included in the differential diagnosis (Table-2).Although in most patients the extent of SHML does not appear to determine disease outcome, recent reports have documented that infiltrates of SHML can cause death.
Management of the Rosai-Dofman disease has no ideal protocol, because it is an uncommon, self-limited disease, frequently requires no therapy. When lymph node or extranodal tissue enlargement causes significant symptoms, such as airway obstruction or compression of vital organs treatment is mandatory. Pulsone at al. reviewed 80 cases published between 1969 and 2000; 50% of these cases required no treatment, of which 82% had full remission18.The role of surgery is mostly for biopsies and to relieve obstruction. Local recurrence is frequent following surgical resection. The role of radiotherapy is not well understood; some reports have described full resolution with this treatment, while others have shown no response1. Steroids often resolve fever and reduce lymph node size. Chemotherapy has yielded controversial results. Further investigations need to study the possible efficacy of methotrexate and 6-mercaptopurine. Use of alpha-interferon has been limited because of its side effects. Higher mortality rate is seen in patients with immunological abnormalities at or before presentation.
If a diagnosis of Rosai–Dorfman disease is made, the patient can be initially observed with the hope of spontaneous remission. For tumours exclusively located in an anatomic site amenable to surgery, surgical excision may be considered when: (i) the lesion persists or recurs; (ii) cytologic findings are inconclusive; or (iii) the patient has symptoms or desire for removal.
References
1. Carpenter RJ III, Banks PM, Mc Donald TJ, Sanderson DR. Sinus histiocytosis with massive Lynphadenopathy (Rosai-Dorfman disease): Report of a case with respiratory tract involvement. Laryngoscope 1978;88:1963-9.
2. Cheng SP, Jeng KS, Liu CL. Subcutaneous Rosai-Dorfman disease: is surgical excision justified? J Eur Acad Dermatol Venereol. 2005;19:747-50.
3. Chu P, LeBoit PE. Histologic features of cutaneous sinus histiocytosis (Rosai-Dorfman disease): study of cases both with and without systemic involvement. J Cutan Pathol 1992; 19: 201–206.
4. Deodhare SS, Ang LC, and Bilbao JM. Isolated intracranial involvement in Rosai-Dorfman disease: a report of two cases and a review of the literature. Arch Pathol Lab Med 1998; 122: 161-165.
5. Donald V. La Barge III,Karen L. Salzman,H. Ric HarnsbergerSinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease): Imaging Manifestations in the Head and Neck AJR:191; December 2008;299-306.
6. Eiras JC, Schettini APM, de Lima LL. Cutaneous Rosai-Dorfman disease ; a case report. An Bras Dermatol. 2010;85(5):687-690
7. Eisen R N, Buckley PJ, Rosai J: Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy (Rosai- Dorfman disease): Semin Diagn Patho 1990;7:74.
8. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990; 7:19–73
9. GULL MOHD BHAT, SURENDER KUMAR, ATUL SHARMA, Rosai-dorfman disease : a case report with review of literature. Indian journal of medical & paediatric oncology 2004 vol. 25 no.4; 39-41.
10. H Y Huang,, C L Yang, W J Chen Rosai-Dorfman Disease with Primary Cutaneous Manifestations—A Case Report,Ann Acad Med Singapore 1998; 27:589-93
11. Hazarika P, Nayak DR, Balakrishnan R, Kundaje HG, Rao PL. Rosai-Dorfman disease of the subglottis. J Laryngol Otol 2000; 114:970-3.
12. Huang HY, Yang C L, Chen W J Rosai-Dorfman Disease with Primary Cutaneous Manifestations—A Case Report Annals Academy of Medicine July 1998, Vol. 27 No. 4: 589-91.
13. Jaffe R,Vaughan De.,Langhoff E:Fascin and differential diagnosis of childhood histiocytic lesions. Pediatrol &Dev Pathol 1998;1:216.
14. Juskevicius R, and Finlay JL. Rosai-Dorfman disease of the parotid gland, cytologic and histopathologic findings with immunohistochemical correlation. Arch Pathol Lab Med 2001; 125: 1348-1350. 

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