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.