A. Introduction

1. Includes various types of Cutaneous T Cell Lymphoma (CTCL)
2. Mycosis fungoides (MF) is most common primary lymphoma of skin
3. In USA, 6.4 cases per 1 million persons annually; >70% of these are mycosis fungoides (MF)

B. Pathogenesis

1. Neoplastic proliferation of mature CD4+ T helper cells
2. T cells express Various Skin Homing Receptors
   1. CLA (cutaneous lymphocyte antigen) - main homing receptor to skin
   2. CCR4 on T cells binds CCL17 on basal keratinocytes and skin endothelium
   3. CCR4 also binds CCL22 on Langerhan's Cells
   4. CXCR3 on T cells ginds IFNg-inducible protein 10 on basal keratinocytes
   5. Integrin alpha-E/beta7 on T cells binds E-cadherin on skin cells
   6. LFA-1 on T cells binds ICAM-1 on endothelium, Langerhan's cells
3. T cells are in an activated state, express IL2alpha receptor (CD25)
   1. Increased levels of IL4 and IL5
   2. IL4 leads to allergic disease and atopy
   3. IL5 leads to eosinophilia
   4. IL10 and TGFß increases can lead to general immunosuppression
4. Malignant T cells are generally clonal with expansion early on of malignant clone
5. Initiating events have not been determined

C. Clinical Progression

1. Mycosis Fungoides (MF)
   1. Nonspecific, erythematous, scaly, eczematous eruption
   2. Gradual progression to symptomatic, thicker, scaly annular plaques
   3. Occasionally, frank tumors occur
   4. Rarely lesions are atrophic and dyspigmented
   5. Lesions can last for months to years
   6. Some patients progress to erythroderma (called erythrodermic MF)
   7. Few or no abnormal T cells in ther blood
2. Accelerated Phase of Disease
   1. Skin tumors
   2. Lymph node involvement
   3. Diffuse metastases
   4. Accelerated phase associated with median survival of <2.5 years
3. Sezary Syndrome
   1. Rare, leukemic variant of MF (T4 classification)
   2. Classically required erythroderma, lymphadenopathy and other systemics, and leukemia
   3. Erythroderma means >80% of skin surface covered with tumor, redened
   4. The leukemia is now defined by flow cytometric evidence of large clonal population
   5. Nnew definition is leukemia (flow cytometric monoclonal population) with erythroderma
   6. Median survival ~ 5 years
4. B cell lymphomas and acute lymphocytic leukemia can present as skin lesions as well

D. Classification [1,2]

1. Indolent
   1. MF - usually CD4+, monoclonal populations; CD8+ also occur, mainly in children
   2. MF and fullicular mucinosis (folliculotrophic)
   3. Pagetoid reticulosis
   4. Primary cutaneous anaplastic large-cell lymphoma
   5. Lymphomatoid papulosis
2. Aggressive
   1. Sezary Syndrome
   2. Peripheral T cell lymphoma (variants: immunoblastic, pleomorphic)
   3. Non-EBV associated hepatosplenic T cell lymphoma associated with transplant - one of the post-transplant lymphoproliferative diseases (PTLD) [3]
3. Provisional
   1. Granulomatous slack skin
   2. CTCL, pleomorphic, small-to-medium size
   3. Subcutaneous panniculitis-like T cell lymphoma
4. Subcutaneous Panniculitis-Like T Cell Lymphoma [5]
   1. Uncommon disorder resembling panniculitis
   2. Prominent systemic symptoms, particularly recurrent fever
   3. Multiple indurated, subcutaneous nodules or plaques, usually in legs, 1-10cm
   4. May be indolent or rapidly progressive
   5. Rapidly progressive may be associated with hemophagocytic syndrome
   6. Lesions show atypical lymphocytes (mainly activated CD+ T cells) and karyorrhexis

E. Classic TNM Staging [1]

1. Tumor (T)
   1. T1: patches, plaques or both <10% of body surface area
   2. T2: pattches, plaques or both at least 10% of body surface area
   3. T3: at least one cutaneous tumor
   4. T4: Erythroderma
2. Lymph Nodes (N)
   1. N0: LN clinically uninvolved
   2. N1: LN clinically enlarged, not histologically involved
   3. N2: LN clinically nonpalpable but histologically involved
   4. N3: LN clinically enlarged and histologically involved
3. Metastasis (M)
   1. M0: no visceral disease
   2. M1: visceral disease
4. Sezary Cells
   1. B0: no circulating atypical (Sezary) cells
   2. B1: circulating atypical cells
5. Staging
   1. IA: T1 N0 M1
   2. IB: T2 N0 M0
   3. IIA: T1-2 N1 M0
   4. IIB: T3 N0-1 M0
   5. IIIA T4 N0 M0
   6. IIIB T4 N1 M0
   7. IVA: Tany N2-3 M0
   8. IVB: Tany Nany M1

F. Algorithm for Early MF Diagnosis [2]

1. Clinical Criteria
   1. Basic: Persistent and/or progressive patches or thin plaques
   2. Additional: non-sun exposed location, variation in size or shape, poikiloderma
   3. Scoring; 2 points for basic criteria and 2 additional criteria OR
   4. 1 point for basic criteria and 1 additional criterion
2. Histopathological Criteria
   1. Basic: Superficial lymphoid infiltrate
   2. Additional: Epidermotropism without spongiosis, lymphoid atypia
   3. Scoring; 2 points for basic criteria and 2 additional criteria OR
   4. 1 point for basic criteria and 1 additional criterion
3. Molecular Biological Criteria
   1. Clonal T cell receptor (TCR) gene rearrangement
   2. Scoring: 1 point
4. Immunopathological Criteria:
   1. <50% CD2+, CD3+ and/or CD5+ T lymphocytes
   2. <10% CD7+ T cells
   3. Epidermal or dermal discordance of CD2, CD3, CD5 or CD7
   4. Scoring: 1 point for one or criteria

G. Treatment of CTCL [1,3,4]

1. Initial Therapy (T1 and T2)
   1. Topical glucocorticoids
   2. Topical nitrogen mustard (mechlorethamine, Mustargen® or carmustine, BiCNU)
   3. Phototherapy
   4. Bexarotene gel (T1) or oral (T2)
   5. Electron beam radiotherapy locally
   6. Methotrexate (T2)
2. Treatment of T3 Disease
   1. Total skin electron beam therapy with or without local radiotherapy
   2. Oral bexarotene
   3. Denileukin diftitox
3. Treatment of T4 Disease
   1. Similar to T3 disease
   2. Chlorambucil (oral)
   3. Extracorporeal photochemotherapy
   4. Interferon alpha
   5. PUVA with interferon alpha
4. Chemotherapy for Resistant Disease
   1. Multiple agents usually used, often initially topical treatments
   2. May be combined with interferon alpha (IFNa)
   3. Vorinostat is approved for progressive, resistant or recurrent CTCL (see below)
   4. Chemotherapy has 10-40% complete responses with higher partial responses
   5. Remission duration highly variable but rarely lasting
   6. Overall little improvement on survival
5. PUVA (Psoralen with UVA) is quite effective in some patients
   1. Some long lasting remissions
   2. Combination with interferons
   3. Very effective for improving skin symptoms
6. Retinoids [4]
   1. Bexarotene (Targretin®) oral formulation 300mg/m2 initial dose now FDA approved
   2. Bexarotene binds retinoic acid X receptor, may induce apoptosis
   3. Causes hyperlipidemia and hypothyroidism; either may require treatment
   4. Complete responses in 5-10%; partial responses in ~50%
7. Denileukin Difitox (Ontak®) [5]
   1. IL2 fusion with fragment of diphtheria toxin
   2. Used for CD25 (IL2 receptor) expressing lymphomas and leukemias
   3. Dose is 9-18µg/kg qd for 5 days every 3 weeks
   4. Vascular leak syndrome may occur
8. Vorinostat (Zolinza®) [10]
   1. Oral histone deactylase (HDAC) inhibitor
   2. Deacetylation of histones leads to inhibition of gene expression
   3. Inhibition of HDAC increases gene expression, including genes involved cell growth
   4. Exact mechanism of action is unclear
   5. In multicenter open-label study, 400mg/day vorinostat in patients with advanced CTCL lead to an overall response rate of ~30%
   6. Fatigue, diarrhea, nausea (>40%), anorxia, weight loss
   7. Thrombocytopenia in ~25%
   8. Pulmonary embolism occurred in 4 of 86 patients
9. Curative regimens for progressive disease have not been developed to date

1. Very aggressive tumors with median survival <4 years
2. Spectrum of ~15 disorders with marked difference sin biology and behavior
   1. Epstein-Barr Virus (EBV) strongly associated with various T cell lymphoma types
   2. Human T cell lymphotropic virus type 1 (HTLV-1) associated with some cases
3. EBV associated disease expresses EBV EBNA-1, LMP-1 and -2
4. Lymphoma and leukemia often coexist

B. T Cell Chronic Lymphocytic Leukemia (T-CLL)

1. Characteristics
   1. Represents 5-10% of CLL cases
   2. T-CLL (mature T cells) and T-cell prolymphocytic leukemia (T-PLL) described
   3. Cells have T cell receptor (TCR) rearrangements
   4. Usually express CD5 marker (similar to B-CLL)
   5. Highly elevated peripheral cell counts typical (>200K/µL in many cases)
2. Clinical Presentation
   1. Splenomegaly and/or hepatomegaly very common
   2. Anemia and thrombocytopenia <50% of patients
   3. Mucosal and cutaneous manifestations common
   4. Pleural effusions and ascites often occur
3. Molecular Genetics [7]
   1. Nearly all cases involve activation of the TCL1 locus on chromosome 14q32.1
   2. TCL1 activation usually due to translocations or inversions involving locus
   3. Four genes in the TCL1 locus are overexpressed in T-CLL
   4. These include TCL1, TCL1b, TNG1, TNG2
   5. Tcl1 protein involved in Akt (protein kinase B) survival pathway
   6. Tcl1 is an oncogene

C. Treatment

1. Generally poor response to therapy overall
2. Strong consideration to experimental regimens should be considered
3. Denileukin difitox for IL2R (CD25) expressing tumors
4. High dose chemotherapy with stem cell rescue may be curative for aggressive forms [8]
5. Nelarabine (Arranon®): prodrug of deoxyguanosine, approved 3rd line, indolent forms [9]

References

1. Girardi M, Heald PW, Wilson LD. 2004. NEJM. 350(19):1979
2. Hwang ST, Janik JE, Jaffe ES, Wilson WH. 2008. Lancet. 371(9616):945
3. Abrahamson JS, Kotton CN, Elias N, et al. 2008. NEJM. 358(11):1176 (Case Record)
4. Bexarotene. 2000. Med Let. 42(1075):31
5. Jacobson JO and De Leval L. 2001. NEJM. 345(19):1409 (Case Record)
6. Thorley-Lawson DA and Gross A. 2004. NEJM. 350(13):1328
7. Pekarsky Y, Hallas C, Croce CM. 2001. JAMA. 286(18):2308
8. Milpied N, Deconinck E, Gaillard F, et al. 2004. NEJM. 350(13):1287
9. Nelarabine. 2006. Med Let. 48(1228):14
10. Vorinostat. 2007. Med Let. 49(1256):23