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. Use terminology and criteria consistent with WHO classification
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. CD30-POSITIVE CUTANEOUS LARGE T-CELL LYMPHOMA
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. N.B. ANAPLASTIC or LARGE CELL HAS NO EFFECT ON OUTCOME
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. DIFFERENTIAL DIAGNOSIS
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. PRIMARY CUTANEOUS CD30-POSITIVE LYMPHOPROLIFERATIVE DISORDERS:
A SPECTRUM OF DISEASE
LyP
BORDERLINE LESIONS
CD30+ LTCL
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. SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA
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 IMMUNOPHENOTYPE 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

51. NODULAR PATTERN vs CTCL
Solitary lesions favour pseudolymphoma
Admixture of CD4+ & CD8+ T-cells
CD4+ usually > CD8+
Numerous small round T-cells
Numerous B-cells (up to 10%)
Numerous histiocytes

52. USEFUL ADDITIONAL FINDINGS
ABERRANT PHENOTYPE
1.Loss of pan-T-cell antigens
CD2, CD3, CD5, CD7
BUT also lost in some benign conditions (esp CD7)
2. Ratio of CD4:CD8
vast excess
dual expression
no expression
MONOCLONAL TCR RE-ARRANGEMENT
BUT monoclonality found in typically benign lesions
e.g. lichen planus, pityriasis lichenoides, LSA
thus monoclonal but benign infiltrates may arise in the skin

53. FURTHER READING Rijlaarsdam et al. Cancer 1992; 69: 717
Rijlaarsdam & Willemze. Sem Diagn Pathol 1991; 8: 102
Van Vloten & Willemze. J Eur Acad Dermatol Venereol 2003; 17: 3
Holm et al. J Cutan Pathol 2002; 29: 447