Sinus Histiocytosis with Massive Lymphoadenopathy (Rosai-Dorfman Disease)

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Sinus Histiocytosis with Massive Lymphoadenopathy
(Rosai-Dorfman Disease)

• Clinical Pathology Conference
• November 4, 2005
• Dean Fong, DO

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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

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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

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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

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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

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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

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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

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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 gt F

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Sinus Histiocytosis with Massive Lymphoadenopathy
(SHML)

• Clinical features
• Registry of 423 cases
• Caucasian African
• Asian ? Less common
• Occasional familial cases

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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

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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

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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
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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 lt 1
Gastrointestinal tract lt 1
Heart Giant cell myocarditis, granulomatous myocarditis, foreign lt 1
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Skin Involvement
Firm indurated papules
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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

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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

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Pathology

• Gross
• Yellow-white with frequent capsular and
  pericapsular fibrosis

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Microscopic

• Normal lymph node architecture preserved
• Effacement seen only in pts. with long-standing
  lymphadenopathy
• Lymph node sinuses expanded by proliferation of
  distinctive histiocytes

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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

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Histiocytes
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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

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Emperipolesis
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Emperipolesis
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Emperipolesis
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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

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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
• Gauchers disease
• Hodgkin Lymphoma

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Differential Diagnosis

• Metastatic melanoma
• Carcinoma
• Infections caused by
• Histoplasma
• Mycobacterial organism
• Reactive sinus histiocytosis

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Differential Diagnosis

• Emperipolesis rare outside setting of SHML but is
  seen in reactive, neoplastic histiocytic
  proliferation, LCH

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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

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CD68
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CD68
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Immunohistiologic Studies

• Effector cells in SHML
• Functionally activated macrophages
• Distinct from Langerhans cells, follicular
  dendritic cells, interdigiting dendritic cells

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Immunohistiologic Studies
SHML LCH
S100
CD1a Rare
CD21, CD23, CD35 (markers of dendritic differentiation) -
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Summary of Histiocytoses
Disease 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
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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

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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

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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

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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 a ? long-term remission
• No ideal treatment ? more data needed

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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

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References

• Henter JI, Tondini C et. al., Histiocyte
  disorders, Critical Reviews in Oncology
  Hematology, 2004 50 157-174.
• Mills SE et. al., Sternbergs 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.