Sinus Histiocytosis with Massive Lymphoadenopathy (Rosai-Dorfman Disease)
Clinical Pathology ConferenceNovember 4, 2005
Dean Fong, DO
Disorder of Histiocytic and Dendritic Derivation Spectrum from benign to frank
malignant Problems with diagnosis:
Scarcity of specific markers Lack of consistent means for
detection of monoclonality Clinicopathologic overlap with
reactive and infectious proliferations
Non-Malignant Histocytoses
Group of disorders involving a pathologic increase in the number of histiocytes
Mononuclear phagocytic cells Circulating monocyte Alveolar macrophages of the lung Kupffer cells of the liver Osteoclasts Microglial cells
Non-Malignant Histocytoses Mainly-antigen presenting cells
Interdigiting reticulum cells and dendritic reticulum cells in the spleen and lymph nodes
Langerhans cells in skin and bronchial epithelium
Bone marrow origin
Non-Malignant Histocytoses Three group of disease
Dendritic cell-related histiocytoses Langerhans cell histiocytoses
Histiocytosis X Eosinophilic granuloma Hand-Schuller-Christian disease Letterer-Siwe disease Single system disease Multisystem disease
Juvenile xanthogranuloma-dermal dendrocyte phenotype
Non-Malignant Histocytoses Three group of disease (cont.):
Macrophage-related histiocytoses Hemophagocytic Lymphohistiocytosis
Primary hemophagocytic lymphohistiocytosis or familial hemophagocytic lymphohistiocytosis Sporadic or familial Associated with infection
Secondary hemophagocytic lymphohistiocytosis Infection-associated hemophagocytic syndrome Malignancy associated hemophagocytic
syndrome Others, including fat overload syndrome
Rosai-Dorfman disease
Sinus Histiocytosis with Massive Lymphoadenopathy (SHML)
First described by Rosai and Dorfman in 1969.
Nonmalignant proliferation of distinctive histiocytic/phagocytic cells within lymph node sinuses and lymphatics in extranodal sites
Sinus Histiocytosis with Massive Lymphoadenopathy (SHML) Clinical features
Worldwide Primarily disease of childhood and early
adulthood Peak age 20 years
Increased incidence of serum auto-immune antibodies during active disease
No specific gender, ethnic, or socioeconomic predilection
Some reports of M > F
Sinus Histiocytosis with Massive Lymphoadenopathy (SHML)
Clinical features Registry of 423 cases:
Caucasian = African Asian Less common Occasional familial cases
Pathogenetic Mechanism Early 3 of 6 cases found serologic evidence
of EBV In 7 of 9 pts. HHV-6 DNA found Unfavorable outcome in patients with immune
dysfunction Exuberant response of hematopoietic system to
undetermined immunologic trigger ? Defective Fas/FasL signaling leading to
defective apoptosis ? histiocytic proliferation
Sinus Histiocytosis with Massive Lymphoadenopathy (SHML)
Most frequent presenting symptoms Cervical region painless
lymphadenopathy Up to 90% of cases
Axillary, para-aortic, inguinal and mediastinal lymph nodes are commonly affected
Extranodal disease in 43% of patients
From the SHML Registry:Anatomic Site Differential Diagnosis Frequency
Lymph nodes CA, melanoma, HL, NHL, infectious, reactive lymphadenopathy, other histiocytoses
(including Langerhans cell histiocytosis)
87%
Skin and Soft tissue Langerhans cell histiocytosis 16%
Nasal cavity/Paranasal sinuses Nasal polyps, nasopharyngeal CA, lymphoma, rhinoscleroma
16%
Eye/Orbit/Ocular adenxa 11%
Bone Langerhans cell histiocytosis 11%
Salivary Gland 7%
Central nervous system Significant diagnostic and therapeutic challenge, usually occurring without extracranial lymphadenopathy and resemble meningioma (clinically and radiologically)
7%
From the SHML Registry:Anatomic Site Differential Diagnosis Frequency
Oral cavity 4%
Kidney/Genitourinary tract 3%
Respiratory tract/Larynx/Lungs
Granulomatous inflammation (including sarcoid, infectious,
Erdheim-Chester disease, foreign body, aspiration pneumonia)
3%
Liver 1%
Tonsil EBV lymphoproliferative disorder, infectious mononucleosis
1%
Breast < 1%
Gastrointestinal tract < 1%
Heart Giant cell myocarditis, granulomatous myocarditis,
foreign
< 1%
Skin Involvement
Firm indurated papules
Sinus Histiocytosis with Massive Lymphoadenopathy (SHML)
Antecedent non-specific fevers and pharyngitis may herald the onset of SHML Occasionally accompanied by pain,
tenderness, malaise, night sweats or weight loss
Pathological Features Laboratory findings:
Normocytic or microcytic anemia Immunologic abnormalities significant number of pts.
unfavorable prgnosis 90% pts. elevated ESR Most frequent immune dysfunction AIHA Polyarthralgia, RA, glomerulopathies, asthma, DM
complicate SHML Polyclonal hypergammaglobinemia 90% of pts. Rare RF, ANA, reversal of CD4/CD8
Small subset NHL, other histiocytic proliferations, myeloma, melanoma, CA
Reported EBV and HHV-6
Pathology Gross
Yellow-white with frequent capsular and pericapsular fibrosis
Microscopic Normal lymph node architecture
preserved Effacement seen only in pts. with long-
standing lymphadenopathy Lymph node sinuses expanded by
proliferation of distinctive histiocytes
Histiocytes Enlarged round or oval vesicular nuclei with
well defined, delicate nuclear membranes and a single prominent nucleolus
Multilobulated nuclei, nucleus with multiple nucleoli, nuclear atypia rare
Mitoses infrequent but increased mitotic activity can be apparent occasionally
Abundant pale eosinophilic cytoplasm Occasional numerous histiocytes with foamy
cytoplasm may predominat cellular milieu
Histiocytes
Histiocytes Hallmark lymphophagocytosis or
emperipolesis Lymphocytic penetration and movement
within another cell Often housed within vacuoles escape
degradation Plasma cells, PMNs, RBCs may also be present
Emperipolesis
Emperipolesis
Emperipolesis
Other Histopathological Features Plasma cells often aggregated around
post-capillary venules Eosinophils not usually seen if seen,
think: LCH, HL, T-cell lymphoma
Collections of PMNs, eosinophilic microabscess, reactive germinal centers seen but not prominent features
Extranodal sites more fibrosis, and fewer histiocytes with emperipolesis
Differential Diagnosis Langerhans Cell Histiocytosis
Lymph node sinuses expanded by histiocytes seen in both LCH and SHML but…
LCH cells are frequently folded or grooved nuclei and associated with eosinophilic microabscess
Histocytic sarcoma Storage disease
Gaucher’s disease Hodgkin Lymphoma
Differential Diagnosis Metastatic melanoma Carcinoma Infections caused by:
Histoplasma Mycobacterial organism
Reactive sinus histiocytosis
Differential Diagnosis Emperipolesis rare outside setting of
SHML but is seen in reactive, neoplastic histiocytic proliferation, LCH
Immunohistiologic Studies Most useful immunologic marker histiocytes
with expression of S100 Histiocytes
Pan-macrophages antigens CD68, HAM 56, CD14, CD64, CD15
Antigens associated with phagocytosis CD64, Fc receptor for IgG
Lysosomal activity Lysozyme, A1A Immune activation Transfering receptor, IL-2
receptor CD163 hemoglobin scavenger receptor and acute
phase-regulated transmembrane protein found on tissue macrophages and monocytes
CD68
CD68
Immunohistiologic Studies Effector cells in SHML
Functionally activated macrophages Distinct from Langerhans cells, follicular
dendritic cells, interdigiting dendritic cells
Immunohistiologic Studies
SHML LCH
S100 + +
CD1a Rare +
CD21, CD23, CD35 (markers of dendritic differentiation)
- +
Summary of HistiocytosesDisease Histiology CD68
(KP-1)S100 CD1a Birbeck
Granules (EM)
Macrophage
Foamy, epithelioid, multinucleated giant
cells
+ - - -
Erdheim-Chester
Touton giant cells + +/- - -
Rosai-Dorfman
Emperipolesis + + - -
Langerhans Cell
Histiocytosis
Reniform nuclei, eosinophilic cytoplasm
+ + + +
Clinical course and treatment Characterized by spontaneous resolution
in most cases Usually indolent for many years, with
spontaneous regression Do not usually threaten life or organ function
Few pts. disease progressive and require treatment
Some pts. episodes of exacerbation alternating with periods of remission that continue for many years
Clinical course and treatment Persistent lymphadenopathy or
progression Associated with involvement of the kidney,
lower respiratory tract or liver with associated immunologic dysfunction
Poor prognosis
Clinical course and treatment SHML registry 423 cases 17 deaths
Only few pts. warrant treatment no randomized trials
“Wait-and-see” approach Antibiotics or anti-tuberculosis drugs no
response Steroids reduction in lymphoadenopathy
and associated fevers Associated autoimmune conditions usually resolve
as the primary condition responds to steroid therapy
Clinical course and treatment Radiation
3 complete remission 3 persistent SHML 3 death
Chemotherapy 10 no response 2 complete and durable remission
Surgery and radiation 1 complete remission 6 partial remission
High dose interferon α long-term remission No ideal treatment more data needed
Late Sequelae and Follow-Up Few pts. require prolonged or
intermittent treatment with corticosteroids Long term steroid effects
No increased incidence of secondary tumors
Follow-up Monitor disease with clinical examination
and CXR
References Henter JI, Tondini C et. al., “Histiocyte
disorders”, Critical Reviews in Oncology Hematology, 2004; 50: 157-174.
Mills SE et. al., Sternberg’s Diagnostic Surgical Pathology, 4th Ed., 2004; 479.
McClain KL, Natkunam Y, et. al., “Atypical Cellular Disorders”, Hematology 2004.
Weitzmann S, Jaffe F, “Uncommon Histiocytic Disorders: The Non-Langerhans Cell Histiocytosis”, Pediatr Blood Cancer, 2005; 45: 256-264.