1. HANDOUT 2 B-CELL INFILTRATES

2. CASE 6: ADDITIONAL FINDINGS B-cells negative with antibodies to: CD5 CD10 CD23 BCL-6 cyclin D1

3. DIAGNOSIS PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA Synonyms: extranodal marginal zone B-cell lymphoma (WHO) cutaneous immunocytoma (EORTC) cutaneous follicular hyperplasia with monotypic plasma cells (Schmid et al Am J Surg Pathol 1995; 19: 12)

4. CLINICAL Solitary or multiple tumours Good response to XRT; CR common Frequently relapse Excellent prognosis; 5-year survival >95%

5. PCMZL and Borrelia burgdorferi A proportion of PCMZL associated with B. burgdorferi infection. Possibly only in some geographic locations; Highlands of Scotland+ve Austria (Graz/Vienna)+ve USA-ve Tawain-ve

6. PATHOLOGY Diffuse or periadnexal/perivascular infiltrate Reactive germinal centres common Interfollicular/diffuse neoplastic infiltrate marginal zone cells small lymphocytes plasmacytoid/plasma cells Reactive cells histiocytes Eosinphils

7. Immunophenotype CD20, bcl-2 positive CD5, CD10, CD23, bcl-6, cyclinD1 negative CD43 +/- Genetics Trisomy 3 in some t(11;18) not found (c.f. gastric & bronchial MZL)

8. DIFFERENTIAL DIAGNOSIS 1.Other small B-cell lymphomas 2.Cutaneous B-cell pseudolymphoma

9. FURTHER READING Rijlaarsdam et al. Histopathology 1993; 23: 117 Bailey et al. Am J Surg Pathol 1996; 20: 1011 Cerroni et al. Am J Surg Pathol 1997; 21: 1307 Goodlad et al. Am J Surg Pathol 2000; 24: 1279 Wood et al. J Cutan Pathol 2001; 28: 502 Ye et al. Blood 2003; 102: 1012 Chunmei et al. Am J Surg Pathol 2003; 27: 1061

10. CASE 7: ADDITIONAL FINDINGS Stage IE on staging: bone marrow, CT chest & abdomen t(14;18) not found

11. DIAGNOSIS PRIMARY CUTANEOUS FOLLICLE CENTRE CELL LYMPHOMA (EORTC: although most cases included in this category display pure diffuse large cell morphology) Synonyms: Grade 3 follicular lymphoma & diffuse large B-cell lymphoma (WHO: classifying lesion in this way may result in over-treatment)

12. CLINICAL Solitary plaques, tumours, nodules Head & neck (scalp) Respond to local XRT: CR usual Frequent relapse Excellent prognosis: 5-year survival ~100%

13. PATHOLOGY As for nodal follicular lymphoma except: Higher proportion of grade 3 lesions +/- DLBCL Lower incidence of bcl-2 expression (0-60%) t(14;18) rarely found

14. PRIMARY CUTANEOUS FOLLICULAR LYMPHOMA High relapse rate but excellent survival

15. 15/15 PCFL in complete remission at end of follow- up period compared with only 49/87 stage I nodal FL (p<0.01:  2 ). Goodlad et al. Am J Surg Pathol 2002 COMPARISON OF OUTCOME WITH STAGE I NODAL FL: Disease status at end of follow-up

16. DIFFERENTIAL DIAGNOSIS 1.Other small B-cell lymphomas 2.Cutaneous B-cell pseudolymphoma

17. Garcia et al. Am J Surg Pathol 1986; 10: 454 Yang et al. Am J Surg Pathol 2000; 24: 694 Cerroni et al. Blood 2000: 95; 3922 Franco et al. Am J Surg Pathol 2001; 25: 875 Aguilera et al. Mod Pathol 2001; 14: 828 Goodlad et al. Am J Surg Pathol 2002; 26: 733 FURTHER READING

18. CASE 8: ADDITIONAL FINDINGS Confined to skin on staging CD5, CD23, cyclin D1 negative

19. DIAGNOSIS LARGE B-CELL LYMPHOMA OF THE LEG (EORTC) Diffuse large B-cell lymphoma (WHO)

20. DIFFUSE LARGE B-CELL LYMPHOMA ARISING PRIMARILY IN THE SKIN Probably two subtypes Currently best classified as per EORTC on basis of anatomic location: 1.Primary cutaneous follicle centre cell lymphoma This includes cases with true follicular morphology as treatment and outcome are the same 2. Large B-cell lymphoma of the leg

21. Primary cutaneous DLBCL on upper body has significantly better prognosis than primary cutaneous B-cell lymphoma on the leg 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative DSS 050150100200250300 Months Upper body (n=17) Lower body (n=13) [p=0.0047] Goodlad et al. Am J Surg Pathol; In press

22. COMPARED TO PCFCCL/LBCL ON UPPER BODY, LARGE B-CELL LYMPHOMA OF THE LEG: More often female Older age More often multiple lesions Significantly poorer prognosis (5YS 95% Significantly higher incidence of bcl-2 expression (~100%) Less frequent CD10/bcl-6 expression More often large round cells (centroblasts/immunoblasts) than large cleaved cells t(14;18) rare at either site

23. N.B. standard treatment for nodal DLBCL is aggressive CTX (anthracycline based); this would be overtreatment for majority of primary cutaneous DLBCL irrespective of location

24. DIFFERENTIAL DIAGNOSIS 1.CTCL, large cell types, non-epidermotropic 2.T/NK cell lymphomas

25. REFERENCES Vermeer et al. Arch Dermatol 1996 Geelen et al. J Clin Oncol 1998; 16: 2080 Fernandez-Vazquez et al. Am J Surg Pathol 2001; 25: 307 Grange et al. J Clin Oncol 2001; 19: 3602 Fink-Puches et al. Blood 2002; 99: 800 Goodlad et al. Am J Surg Pathol; In press

26. CASE 9: ADDITIONAL FINDINGS Polyclonal kappa/lambda Polyclonal IgH re-arrangement

27. DIAGNOSIS CUTANEOUS B-CELL PSEUDOLYMPHOMA Synonyms: lymphocytoma (benigna) cutis Spiegler-Fendt sarcoid B-cutaneous lymphoid hyperplasia

28. CUTANEOUS B-CELL PSEUDOLYMPHOMA Cutaneous infiltrate histologically simulating CBCL Cliincally may also mimic lymphoma solitary red nodule/plaque (85-90%) generalised/multifocal lesions (10-15%)

29. AETIOLOGY Idiopathic Borrelia burgdorferi Tattoo (red) Injection sites Acupuncture Trauma Vaccination Gold piercing earrings COMMON THEME IS REACTION TO ANTIGEN

30. PATHOLOGY Diffuse or nodular infiltrate (Grenz zone) Reactive polytypic B-cells  Often in nodules +/- germinal centres  T-cell rich areas in between Prominent vasculature Macrophages, plasma cells, eosinophils PRESERVED IMMUNOARCHITECTURE

31. B-cell nodules CD20, CD23 T-cell areas CD3 + few B-cells B-CLH: IMMUNOARCHITECTURE

32. DIFFERENTIAL DIAGNOSIS: CUTANEOUS INFILTRATES RICH IN SMALL B-CELLS 1.B-cell pseudolymphoma 2.Marginal zone lymhpoma 3.Follicular lymphoma 4.(Secondary involvement by: B-CLL Mantle cell lymphoma)

33. NATURE OF LYMPHOID FOLLICLES? 1.REACTIVE FOLLICLES Found in all three but rare in FL Appearance as at other sites  Zonation  Tingible body macrophages  Mitotic figures  Well formed mantles  Uniform CD10/bcl-6 expression by GCCs  Bcl-2 negative

34. 2. COLONISED FOLLICLES Typical of MZL Distinct compartments  Reactive GCC: CD10/bcl-6 +ve, bcl-2 -ve  Neoplastic MZ cells: CD10/bcl-6 -ve, bcl-2 +ve 3. NEOPLASTIC FOLLICLES Only seen in FL Same as in nodal FL  No zonation  Monotonous appearance  Few TBMs, MFs (NB grade 3 FL)  Absent/poorly formed mantles  Uniform CD10/bcl-6 staining  Bcl-2 usually +ve (but significant % -ve cases)

35. NATURE OF INTERFOLLICULAR INFILTRATE? 1.B-CELL PSEUDOLYMPHOMA T-cells >> B-cells NO confluent sheets of B-cells Polytypic light chain immunohistochemistry Epidermal changes  e.g. parakeratosis, atrophy, acanthosis, spongiosis 2. MARGINAL ZONE LYMPHOMA Clusters/sheets of marginal zone cells >75% B-cells Light chain restriction Aberrant CD43 expression

36. 3. FOLLICULAR LYMPHOMA Clusters of CD10/bcl-6+ve B-cells  Useful when bcl-2 –ve  CD10 may be down-regulated

37. POLYMERASE CHAIN REACTION Can be helpful but use limited by: Most FL are t(14;18) negative False negatives relatively common False positive results when very few B-cells Some CBCPL are monoclonal Some CBCPL progress to overt lymphoma

38. THE MOST IMPORTANT DECISION: SHOULD THE PATIENT BE STAGED?

39. FURTHER READING Ritter et al J Cutan Pathol 1994; 21: 481 Baldassano et al. Am J Surg Pathol 1999; 23: 88 de Leval et al. Am J Surg Pathol 2001; 25: 732 Nihal et al. Hum Pathol 2003; 34: 617