1. Sinus Histiocytosis with Massive Lymphoadenopathy (Rosai-Dorfman Disease) Clinical Pathology Conference November 4, 2005 Dean Fong, DO

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Sinus Histiocytosis with Massive Lymphoadenopathy (SHML) Clinical features Registry of 423 cases: Caucasian = African Asian  Less common Occasional familial cases

10. 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

11. 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

12. From the SHML Registry: Anatomic SiteDifferential DiagnosisFrequency Lymph nodesCA, melanoma, HL, NHL, infectious, reactive lymphadenopathy, other histiocytoses (including Langerhans cell histiocytosis) 87% Skin and Soft tissueLangerhans cell histiocytosis16% Nasal cavity/Paranasal sinusesNasal polyps, nasopharyngeal CA, lymphoma, rhinoscleroma 16% Eye/Orbit/Ocular adenxa11% BoneLangerhans cell histiocytosis11% Salivary Gland7% Central nervous systemSignificant diagnostic and therapeutic challenge, usually occurring without extracranial lymphadenopathy and resemble meningioma (clinically and radiologically) 7%

13. From the SHML Registry: Anatomic SiteDifferential DiagnosisFrequency Oral cavity4% Kidney/Genitourinary tract3% Respiratory tract/Larynx/Lungs Granulomatous inflammation (including sarcoid, infectious, Erdheim-Chester disease, foreign body, aspiration pneumonia) 3% Liver1% TonsilEBV lymphoproliferative disorder, infectious mononucleosis 1% Breast< 1% Gastrointestinal tract< 1% HeartGiant cell myocarditis, granulomatous myocarditis, foreign < 1%

14. Skin Involvement Firm indurated papules

15. 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

16. 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

17. Pathology Gross Yellow-white with frequent capsular and pericapsular fibrosis

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

19. 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

20. Histiocytes

21. 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

22. Emperipolesis

25. 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

26. 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

27. Differential Diagnosis Metastatic melanoma Carcinoma Infections caused by: Histoplasma Mycobacterial organism Reactive sinus histiocytosis

28. Differential Diagnosis Emperipolesis rare outside setting of SHML but is seen in reactive, neoplastic histiocytic proliferation, LCH

29. 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

30. CD68

32. Immunohistiologic Studies Effector cells in SHML Functionally activated macrophages Distinct from Langerhans cells, follicular dendritic cells, interdigiting dendritic cells

33. Immunohistiologic Studies SHMLLCH S100++ CD1aRare+ CD21, CD23, CD35 (markers of dendritic differentiation) -+

34. Summary of Histiocytoses DiseaseHistiologyCD68 (KP-1) S100CD1aBirbeck Granules (EM) MacrophageFoamy, epithelioid, multinucleated giant cells +--- Erdheim- Chester Touton giant cells++/--- Rosai- Dorfman Emperipolesis++-- Langerhans Cell Histiocytosis Reniform nuclei, eosinophilic cytoplasm ++++

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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, 4 th 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.