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HANDOUT 1. (INTRODUCTION) T-CELL INFILTRATES. CUTANOEUS LYMPHOID INFILTRATES COMMONLY ASKED QUESTIONS. 1. Is it benign or malignant? Distinguishing benign from neoplastic lymphoid infiltrates in the skin What sort of lymphoma is this? Problems with existing classifications

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  1. HANDOUT 1 (INTRODUCTION) T-CELL INFILTRATES

  2. CUTANOEUS LYMPHOID INFILTRATES COMMONLY ASKED QUESTIONS • 1. Is it benign or malignant? • Distinguishing benign from neoplastic lymphoid infiltrates in the skin • What sort of lymphoma is this? • Problems with existing classifications • Recognizing (very) rare entities

  3. CLASSIFICATION OF CUTANEOUS LYMPHOMA • Modern lymphoma classifications define entities on basis of ALL available information • Morphology • Immunophenotype • Genetic features • Clinical features • Two systems applicable to skin

  4. WHO CLASSIFICATION Site of origin recognised as important in determining characteristics of a lymphoma, but little clinical detail given for B-cell lymphomas arising primarily in the skin EORTC CLASSIFICATION Only includes cutaneous lymphomas. Provides detailed clinical information, including best treatment, but not widely accepted outside Europe CONSIDERABLE OVERLAP BUT TERMINOLOGY AND DEFINITIONAL CRITERIA USED FOR SOME ENTITIES NOT DIRECTLY COMPARABLE

  5. WHICH CLASSIFICATION? • A pragmatic approach • Use terminology and criteria consistent with WHO classification • Include EORTC equivalent in conclusion and/or additional information to highlight lymphoma subtypes which are biologically distinct when arising primarily in skin BOTH!

  6. CASE 1 ADDITIONAL FINDINGS • Phenotype of majority of cells in both biopsies CD3+/CD4+/CD8- • Same clonal TCR re-arrangement in both biopsies

  7. DIAGNOSIS FOLLICULAR MYCOSIS FUNGOIDES MF-associated follicular mucinosis (EORTC) Pilotropic mycosis fungoides Folliculocentric mycosis fungoides CLINICOPATHOLOGICALLY DISTINCT VARIANT OF MYCOSIS FUNGOIDES

  8. CLINICAL FEATURES • Predilection for head and neck • Patches, plaques or grouped papules • Alopecia, pruritis, bacterial infection common • Rare presentations include • nodules/tumours • cysts/comedones • erythroderma

  9. PATHOLOGY (1) • Perivascular/perifollicular or diffuse dermal infiltrate • Lack of epidermotropism • Medium to large T-cells with cerebriform nuclei • Infiltration of hair follicle epithelium • Usually (not always) with follicular mucinosis • Often relatively few infiltrating lymphocytes • Infiltration of sweat duct epithelium rarely

  10. PATHOLOGY (2) • Reactive cells • Small lymphocytes, histiocytes, eosinophils, plasma cells • Disease progression associated with • More diffuse dermal infiltrate • Destruction/loss of hair follicles • Increasing numbers of blasts • Immunophenotype • CD3+/CD4+/CD8- • CD30+ blasts variable

  11. TREATMENT/OUTCOME • Compared to classic MF • Respond less well to skin targeted therapy • (Total skin electron beam in favour of PUVA) • Fewer achieve complete remission regardless of treatment • Much poorer survival than plaque/patch stage MF • Similar survival to tumour stage MF • 5-year DSS = 68%; 10-year DSS = 26%

  12. DIFFERENTIAL DIAGNOSIS • Non-epidermotropic CTCL • Look hard for follicular damage • Idiopathic follicular mucinosis/Alopecia mucinosa • Pseudolymphomatous folliculitis

  13. 2. IDIOPATHIC FOLLICULAR MUCINOSIS • Younger adults, adolescents • Solitary/localised lesions on head & neck • No progression to overt CTCL • NO pathological features which permit D/Dx from follicular mucinosis due to CTCL • histology • immunophenotype • PCR (~50% monoclonal TCR re-arrangement) • A localised variant of follicular MF with excellent prognosis?

  14. 3. PSEUSOLYMPHOMATOUS FOLLICULITIS • Solitary or localised dome shaped lesions on face • Dense dermal infiltrate; variable proportion of T & B cells • Perifollicular distribution • Enlargement & distortion of hair follicles (activation) • Lymphocytic infiltration of epithelium • Aggregates of histiocytes adjacent to follicles (S-100/CD1a positive) • PCR polyclonal • Spontaneous regression may occur following incisional biopsy

  15. FURTHER READING Cerroni et al. Arch Dermatol 2002; 138: 182 Van Doorn et al. Arch Dermatol 2002; 138: 191 Eichii et al. Am J Surg Pathol 1999; 23: 1313

  16. CASE 2: ADDITIONAL FINDINGS • No history of prior or concurrent MF • Localised to skin on staging

  17. DIAGNOSIS CD30-POSITIVE CUTANEOUS LARGE T-CELL LYMPHOMA (EORTC) NOTE: Strict application of WHO classification would result in this case being classified as, ‘peripheral T-cell lymphoma, unspecified’ because cells do not have an anaplastic morphology. This would result in overtreatment: should really be included in category of ‘PRIMARY CUTANEOUS ANAPLASTIC LYMPHOMA’

  18. CLINICAL • Disease of adults; rare in children (cf systemic ALCL) • Nodules or tumours +/- ulceration • 80% solitary or localised • 20% multicentric • Partial/complete spontaneous regression in some

  19. PATHOLOGY • Diffuse non-epidermotropic infiltrate of large T-cells • 80% anaplastic morphology • Round, oval, irregular nuclei • Prominent nucleoli • Abundant cytoplasm • R-S-like cells • 20% large T-cells • Pleomorphic • Immunoblastic N.B. ANAPLASTIC or LARGE CELL HAS NO EFFECT ON OUTCOME

  20. IMMUNOPHENOTYPE/GENETICS • CD4/CD30 positive (>75% cells) • Loss of pan-T-cell antigens (CD2/3/5/7) common but ‘null-cell’ phenotype rare • Cytotoxic granule associated proteins usually positive (>70% cases) • TIA-1 • Granzyme B • perforin • EMA & ALK negative • NO t(2;5)

  21. TREATMENT/OUTCOME • Most cases treatable by XRT or low dose methotrexate (if multicentric) • 5-year survival ~90% • DIFFERENTIAL DIAGNOSIS • Systemic ALCL involving skin • 2. Transformed MF • 3. Lymphomatoid papulosis • 4. Benign lesions with CD30-positive cells

  22. SYSTEMIC ANAPLASTIC LARGE CELL LYMPHOMA • Similar morphology • Bimodal age distribution; affects children • Almost always disseminated at presentation • Different phenotype • ALK+ • EMA+ • t(2;5) present

  23. TRANSFORMED MYCOSIS FUNGOIDES • Biopsy proven history of MF • Infiltrate >25% large T-cells (>x4 small lymphocyte) • In 1/3 cases majority of cells CD30+ • Usually correlates with tumour-stage lesions • Very poor outcome: 5-year survival ~20% • CLINICOPATHOLOGICAL CORRELATION/REVIEW

  24. LYMPHOMATOID PAPULOSIS • Crops of papular, papulonecrotic, nodular skin lesions • Grouped but may be in different stages of development • Spontaneous regression of individual lesion; 3-6 weeks • Chronic but benign course; months-years • 5 year survival ~100% • No treatment required or low dose methotrexate, PUVA or XRT for large, numerous or scarring lesions

  25. PATHOLOGY: TWO TYPES OF LESION • TYPE A • Wedge shaped dermal infiltrate: non-epidermotropic • Large atypical CD30+ T-cells • Histiocytes, small lymphocytes, granulocytes • TYPE B • Simulates plaque-stage MF • Perivascular or band-like epidermotropic infiltrate • Small lymphocytes with cerebriform nuclei • IMMUNOPHENOYPE/GENETICS • Large T-cells: same as for CD30+ LTCL • TCR often clonally rearranged; type B>type A • t(2;5) not found

  26. CD30+ LTCL LyP BORDERLINE LESIONS PRIMARY CUTANEOUS CD30-POSITIVE LYMPHOPROLIFERATIVE DISORDERS: A SPECTRUM OF DISEASE • Discrepancy between clinical features and histology • Sheets of CD30+ large T-cells • Regressing papules • 2. LyP histology • Solitary persistent tumours

  27. BENIGN LESIONS WITH CD30+ CELLS • Drug reaction (carbamazepine) • Viral infection (molluscum, herpes simplex) • Arthropod bite reactions (scabies) • CLINICOPATHOLOGICAL CORRELATION

  28. CD30+ CUTANEOUS INFILTRATES: THREE STEPS TO DIAGNOSIS • Step 1: exclude benign conditions • Step 2: is the lesion primary or secondary? • Hx of prior or concurrent MF • (If localised to skin manage as tumour stage MF; N.B. ~3% of MF have concurrent LyP so make sure lesions don’t spontaneously regress) • ALK/EMA positivity: ALCL; needs systemic CTX • Step 3: LyP or CD30+ LTCL? • In view of ‘borderline cases’ give lesions chance to regress

  29. FURTHER READING Bekkenk et al. Blood 2000; 95: 3653 Beylot-Barry et al. Blood 1998; 91: 4668 Wood et al. Blood 1996; 8: 1765 Whittaker et al. J Invest Dermatol 1991; 96: 786 Nathan & Belsito. J Am Acad Dermatol 1998; 38: 806 McCalmont & LeBoit. Am J Dermatopathol 2000; 22: 188

  30. CASE 3: ADDITIONAL FINDINGS • Confined to skin on staging • Monoclonal TCR-gamma gene re-arrangement

  31. DIAGNOSIS PERIPHERAL T-CELL LYMPHOMA, UNSPECIFIED (WHO) OR PRIMARY CUTANEOUS CD30- LARGE T-CELL LYMPHOMA (EORTC)

  32. PTL, UNSPECIFIED PRESENTING IN SKIN • Heterogeneous group of diseases • Poor prognosis: 5-year survival ~20% • Diffuse, nodular or band-like infiltrate • Variably sized T-lymphocytes • +/- epidermotropism • +/- angiocentricity • Admixture of reactive cells • Histiocytes > eosinophils, plasma cells • B-cells; up to 5-10% of infiltrate • CD3+/CD4+/CD8- > CD3+/CD4-/CD8+ • TIA-1 +/- (CD8+ cases) • CD56 rarely positive • CD30 negative

  33. SUBCLASSIFICATION • Prognosis appears to be influenced by cell size • Overall 5-year survival • Large cells confined to skin 12% • Large cells + lymph node involvement 12% • Small/medium cells confined to skin 45% • (only localised CD4+ cases do well) • EORTC recommend sub-division on basis of cell size • CD30- large T-cell lymphoma • >30% large cells • 2. Small/medium sized CD30- pleomorphic T-cell lymphoma

  34. DIFFERENTIAL DIAGNOSIS • CD30+ large T-cell lymphoma • > or < 75% cells express CD30 • 2. Tumour stage MF • Clinicopathological correlation • 3. Follicular MF • +/- infiltration of hair follicles • 4. Subcutaneous panniculitis-like T-cell lymphoma • 5. Cutaneous T-cell pseudolymphoma

  35. FURTHER READING Bekkenk et al. Blood 2003; 102: 2213 Beljaard et al. J Pathol 1994; 172: 53 Grange et al. Blood 1999; 3637

  36. CASE 4: ADDITIONAL FINDINGS • Immunophenotype • CD3+ • CD8+ • CD4- • CD56- • PCR • Monoclonal TCR gene re-arangement

  37. DIAGNOSIS SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA (EORTC, WHO) Synonyms cytophagic histiocytic panniculitis

  38. CLINICAL • Multiple skin nodules • +/- ulceration • Often tender • Trunk, extremities • Systemic symptoms due to haemophagocytic syndrome in some • Pancytopaenia • Fever • Hepatospelonmegaly

  39. PATHOLOGY • Preferential involvement of subcutis • Resembles panniculitis with lobular & septal involvement • Dermis only occasionally involved (CD56+, g/d) • Variably sized neoplastic lymphocytes • Rimming of fat cells • Tumour cell necrosis, histiocytes, erythrophagocytosis IMMUNOPHENOTYPE • Lymphoma of cytotoxic T-cells • CD3+, CD8+, CD4- • TIA-1, granzyme , perforin (cytotoxic molecules) • CD16, CD30, CD56 (except for g/d cases), CD57 negative • EBV negative

  40. PROGNOSIS • Aggressive but usually good response to CTX • CD56+ cases seem to do badly

  41. DIFFERENTIAL DIAGNOSIS • CD30- CTCL/peripheral T-cell lymphoma unspecified • Distribution of infiltrate; dermis vs subcutis • Rimming of fat cells, karryhorexis • Most CD30- CTCL are also CD8- • 2. Nasal NK/T cell lymphoma • Usually involves other extranodal sites • Prominent angiocentricity • Overruns rather than rims fat cells • CD2/CD56+, CD3-, CD3e+ (cytoplasmic) • EBV+ • TCR usually germline

  42. FURTHER READING Salhany et al. Am J Surg Pathol 1998; 22: 881 Chan et al. Mod Pathol 1996; 9: 109 Gonzalez et al. Am J Surg Pathol 1991; 15: 17 Santucci et al. Cancer 2003; 97: 610

  43. CASE 5: ADDITIONAL FINDINGS • Polyclonal TCR re-arrangement • Patient found to be on ACE inhibitor

  44. DIAGNOSIS CUTANEOUS T-CELL PSEUDOLYMPHOMA (drug induced) Synonyms: lymphomatoid drug reaction T-cutaneous lymphoid hyperplasia

  45. CUTANEOUS T-CELL PSEUDOLYMPHOMA • Definition • Lymphoid infiltrate highly suggestive of CTCL • Clinical features NOT consistent with CTCL • Identification of causative agent • Uncommon presentation or course

  46. CUTANEOUS T-CELL PSEUDOLYMPHOMA: SUBTYPES • Well defined clinicopathological entities • Drug induced • Anticonvulsants; phenytoin, carbamazepine • ACE inhibitors • Miscellaneous; atenolol, allopurinol, mexilitine, cyclosporine, antihistamines, griseofulvin • Insect bite reactions • Lymphomatoid contact dermatitis • Actinic reticuloid; • chronic photosensitive dermatitis • Scaly erythema of exposed skin • 2. Idiopathic

  47. HISTOLOGY: TWO PATTERNS • Band-like infiltrate (MF-like) • Subepidermal infiltrate • Atypical medium sized cerebriform cells • +/- blasts • histiocytes • Few/no eosinophils, plasma cells • Seen in all types of CTCPL except insect bite reactions

  48. 2. Nodular pattern • Many small round T-cells • Scattered T-blasts & medium/large cerebriform cells • Histiocytes usually numerous +/- plasma cells, eosinophils • Seen in • Drug induced CTCPL • Persistent arthropod bite reactions • Idiopathic CTCPL

  49. MF-LIKE CTCPL vs MYCOSIS FUNGOIDES • Features which strongly suggest MF • Pautrier’s microabscesses • Medium/large cerebriform cells in epidermis • Linear epidermotropism • Disproportionate epidermotropism • ‘Haloed’ lymphocytes in epidermis

  50. ACTINIC RETICULOID vs MYCOSIS FUNGOIDES • CD8+ T-cells, MF usually CD4+ • Multinucleate giant cells • fibroblasts • histiocytes • Vertically orientated collagen in papillary dermis

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