Transcript Sinus Histiocytosis with Massive Lymphoadenopathy (Roasi

Sinus Histiocytosis with
Massive Lymphoadenopathy
(Rosai-Dorfman Disease)
Clinical Pathology Conference
November 4, 2005
Dean Fong, DO
Disorder of Histiocytic and
Dendritic Derivation
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Spectrum from benign to frank
malignant
Problems with diagnosis:
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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
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Circulating monocyte
Alveolar macrophages of the lung
Kupffer cells of the liver
Osteoclasts
Microglial cells
Non-Malignant Histocytoses
Mainly-antigen presenting cells
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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
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Dendritic cell-related histiocytoses
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Langerhans cell histiocytoses
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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.):
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Macrophage-related histiocytoses
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Hemophagocytic Lymphohistiocytosis
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Primary hemophagocytic lymphohistiocytosis or familial
hemophagocytic lymphohistiocytosis
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Sporadic or familial
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Associated with infection
Secondary hemophagocytic lymphohistiocytosis
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Infection-associated hemophagocytic syndrome
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Malignancy associated hemophagocytic syndrome
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Others, including fat overload syndrome
Rosai-Dorfman disease
Sinus Histiocytosis with Massive
Lymphoadenopathy (SHML)
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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)
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Clinical features
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Worldwide
Primarily disease of childhood and early adulthood
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Peak age  20 years
Increased incidence of serum auto-immune
antibodies during active disease
No specific gender, ethnic, or socioeconomic
predilection
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Some reports of M > F
Sinus Histiocytosis with Massive
Lymphoadenopathy (SHML)
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Clinical features
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Registry of 423 cases:
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Caucasian = African
Asian  Less common
Occasional familial cases
Pathogenetic Mechanism
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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
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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)
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Most frequent presenting symptoms
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Cervical region painless lymphadenopathy
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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
Bone
11%
Langerhans cell histiocytosis
Salivary Gland
Central nervous system
11%
7%
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)
Liver
Tonsil
3%
1%
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)
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Antecedent non-specific fevers and
pharyngitis may herald the onset of
SHML
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Occasionally accompanied by pain,
tenderness, malaise, night sweats or
weight loss
Pathological Features
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Laboratory findings:
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Normocytic or microcytic anemia
Immunologic abnormalities  significant number of pts. 
unfavorable prgnosis
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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
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Gross
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Yellow-white with frequent capsular and
pericapsular fibrosis
Microscopic
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Normal lymph node architecture preserved
Effacement seen only in pts. with longstanding lymphadenopathy
Lymph node sinuses expanded by
proliferation of distinctive histiocytes
Histiocytes
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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
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Occasional numerous histiocytes with foamy cytoplasm may
predominat cellular milieu
Histiocytes
Histiocytes
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Hallmark  lymphophagocytosis or
emperipolesis
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Lymphocytic penetration and movement within
another cell
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Often housed within vacuoles  escape degradation
Plasma cells, PMNs, RBCs  may also be present
Emperipolesis
Emperipolesis
Emperipolesis
Other Histopathological Features
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Plasma cells often aggregated around postcapillary venules
Eosinophils not usually seen  if seen, think:
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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
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Langerhans Cell Histiocytosis
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Lymph node sinuses expanded by histiocytes seen
in both LCH and SHML but…
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Histocytic sarcoma
Storage disease
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LCH cells are frequently folded or grooved nuclei and
associated with eosinophilic microabscess
Gaucher’s disease
Hodgkin Lymphoma
Differential Diagnosis
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Metastatic melanoma
Carcinoma
Infections caused by:
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Histoplasma
Mycobacterial organism
Reactive sinus histiocytosis
Differential Diagnosis
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Emperipolesis rare outside setting of SHML
but is seen in reactive, neoplastic histiocytic
proliferation, LCH
Immunohistiologic Studies
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Most useful immunologic marker  histiocytes with
expression of S100
Histiocytes
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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 phaseregulated transmembrane protein found on tissue
macrophages and monocytes
CD68
CD68
Immunohistiologic Studies
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Effector cells in SHML
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Functionally activated macrophages
Distinct from Langerhans cells, follicular dendritic
cells, interdigiting dendritic cells
Immunohistiologic Studies
SHML
LCH
S100
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CD1a
Rare
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CD21, CD23,
CD35 (markers
of dendritic
differentiation)
Summary of Histiocytoses
Disease
Histiology
CD68
(KP-1)
S100
CD1a
Birbeck
Granules
(EM)
Macrophage
Foamy, epithelioid,
multinucleated giant
cells
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ErdheimChester
Touton giant cells
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+/-
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RosaiDorfman
Emperipolesis
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+
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Langerhans
Cell
Histiocytosis
Reniform nuclei,
eosinophilic cytoplasm
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Clinical course and treatment
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Characterized by spontaneous resolution in
most cases
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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
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Persistent lymphadenopathy or progression
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Associated with involvement of the kidney, lower
respiratory tract or liver with associated
immunologic dysfunction
Poor prognosis
Clinical course and treatment
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SHML registry  423 cases  17 deaths
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Only few pts. warrant treatment  no randomized
trials
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“Wait-and-see” approach
Antibiotics or anti-tuberculosis drugs  no
response
Steroids  reduction in lymphoadenopathy and
associated fevers
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Associated autoimmune conditions usually resolve as the
primary condition responds to steroid therapy
Clinical course and treatment
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Radiation
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Chemotherapy
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10  no response
2  complete and durable remission
Surgery and radiation
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3  complete remission
3  persistent SHML
3  death
1  complete remission
6  partial remission
High dose interferon α  long-term remission
No ideal treatment  more data needed
Late Sequelae and Follow-Up
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Few pts. require prolonged or intermittent
treatment with corticosteroids
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Long term steroid effects
No increased incidence of secondary tumors
Follow-up
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Monitor disease with clinical examination and CXR
References
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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.