Sinus Histiocytosis with Massive Lymphoadenopathy (Rosai-Dorfman Disease)

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:

13. From the SHML Registry:

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. 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

22. Emperipolesis

23. Emperipolesis

24. 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

31. CD68

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

33. Immunohistiologic Studies

34. Summary of Histiocytoses

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, 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.