ACADEMY MEETING American Academy of Dermatology San Diego CA Forum

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ACADEMY MEETING American Academy of Dermatology San Diego CA Forum Powered By Docstoc
					    ACADEMY ’06 MEETING
American Academy of Dermatology
         San Diego, CA

        Forum #506
CUTANEOUS T-CELL LYMPHOMA
           July 27, 2006


        Youn H. Kim, MD
      Uma Sundram, MD, PhD
CTCL Update
• Clinical Features
   – Clinical clues for diagnosis, staging and prognosis
      • Youn Kim, Professor of Dermatology, Stanford University School of Medicine
• Pathology
   – Histopathologic diagnosis, role of IHC/molecular techniques
      • Uma Sundram, Assistant Professor of Pathology & Dermatology, Stanford
        University School of Medicine

• Therapy
   – Topical, systemic, combined modality, and investigative
     therapies
      • Youn Kim
Classification, Clinical Presentation,
     Staging and Prognosis in
   Cutaneous T-Cell Lymphoma




                  Youn H. Kim
           Department of Dermatology
   Multidisciplinary Cutaneous Lymphoma Group
      Stanford University School of Medicine
Disclosure of Conflict of Interest

Youn H. Kim, M.D.
Forum #506
  Cutaneous T-cell Lymphoma
  July 27, 2006



  Co-investigator in clinical trials sponsored by BioCryst,
  Coley/Pfizer, Aton/Merck, Curagen, Gloucester, Genmab, Seagen,
  Therakos; Honorarium/grants from Scimed, Merck, Ligand,
  Ovation
Multidisciplinary Cutaneous Lymphoma Clinic/Program
Youn Kim                                      Director, Dermatology
Richard Hoppe                                 Co-Director, Radiation Oncology
Ranjana Advani, Sunil Reddy                   Medical Oncology
Sabine Kohler, Uma Sundrum, David Cassarino   Dermatopathology
Sunil Reddy, Anjali Varma                     Cutaneous Lymphoma Fellows
Natalie Viakhireva                            Physician Assistant
Katherine Sutherland                          Research Assistant
Carol Bruce                                   Nurse Coordinator
Dermatology Residents

Web Site: cutaneouslymphoma.stanford.edu
Cutaneous T- and NK/T-cell Lymphomas
New WHO-EORTC Classification

Mycosis fungoides and variants/subtypes

Sézary syndrome

PC CD30+ lymphoproliferative disorders

Subcutaneous panniculitis-like T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Adult T-cell leukemia/lymphoma
PC peripheral T-cell lymphoma, unspecified
   • Aggressive epidermotropic CD8+ T-cell lymphoma
   • Cutaneous γ/δ T-cell lymphoma
                                                        Blood
   • PC CD4+ sm/med-sized pleomorphic T-cell lymphoma   2005;105:
   • PTCL, other                                        3768-85
Cutaneous B-cell Lymphomas

New WHO-EORTC Classification

Marginal zone B-cell lymphoma



Follicle center lymphoma



Diffuse large B-cell lymphoma, leg-type

Diffuse large B-cell lymphoma, other
Mycosis Fungoides, “CTCL”

• Extranodal non-Hodgkin’s lymphoma of mature T-cells (CD3+) with
  primary cutaneous involvement
• Spectrum of skin presentation from indolent patch/plaque disease
  to tumors and erythroderma, many clinical variants
• Epidermotropic, clonal, malignant process of mostly CD4+ T-cells
   – Sub-type of CD8+ MF
• Unknown etiology
   – Evidence against a role for HTLV-I (JID 107:301, 1996)
Clinical Characteristics of 525 Patients with MF/SS: Stanford data
                                                                  Arch Dermatol,
        Characteristics                              Values       2003
        Age by T-classification, median (range), y
               All patients, n=525                   57 (12-88)
               T1, n=159 (30%)                       49 (22-82)   Young Pts,
                                                                  Stanford data,
               T2, n=192 (37%)                       58 (12-88)   Crowley,
               T3, n=96 (18%)                        58 (19-86)   JAAD, 1998
               T4, n=78 (15%)                        65 (36-87)
        Gender, No.(%)
               Female                                195 (37)
               Male                                  330 (63)
        Race, No. (%)
               Asian                                 10 (2)
               Black                                 20 (4)
               Latino                                43 (8)
               White                                 452 (86)
Mycosis Fungoides
Clinical & Histologic Variants/Subtypes – Unique Prognosis?
•   Hypopigmented/vitiligenous MF
•   Pagetoid reticulosis (Woringer-Kolopp type only)
•   Follicular MF (+/- mucinosis)
•   Granulomatous MF
    – Granulomatous slack skin
•   Bullous MF
•   PPE-like MF
•   Interstitial MF (J Cutan Pathol, 29:135-141, 2002)
•   Papular MF
•   Icthyiosiform MF
Sézary Syndrome

• Erythrodermic, leukemic variant of CTCL
• Generalized erythroderma, lymphadenopathy, circulating atypical
  T-cells (Sézary cells)
• Criteria of blood involvement in Sézary syndrome
The Criteria for Significant Blood Involvement (B Classification),

Consensus Report by ISCL, Vonderheid et al, JAAD 46,95, 2002
•   Criteria for blood involvement is becoming up-to-date with current tissue
    diagnostic criteria for MF/CTCL, not defined by morphology alone
•   B0, no PBSC by morphology, immunologic or molecular parameters
•   B1, PBSC > 20%, < 1,000 /mm3 by morphology, lack of B2 parameters
•   B2, Sézary syndrome, 1 or more of following parameters
    – Morphology, PBSC > 1,000 /mm3
    – Immunophenotypic abnormalities (flow cytometry)
        • CD4/CD8 ratio > 10 (setting of an expanded CD4)
        • CD4+CD7- cells > 40% or CD4+CD26- >30% of lymphocytes
        • Other aberrant expression of pan T-cell markers
    – Lymphocytosis (>5-20% lymph) + T-cell clonality (relevant clone)
•   Ongoing multi-center project to test the ISCL and others’ proposals
Staging Evaluation, Mycosis Fungoides
•   Thorough skin examination
•   Comprehensive general physical
    examination
•   Complete blood count with Sézary cell
    analysis
•   Screening chemistries, LDH, urinalysis
•   Chest x-ray
•   If significant lymphadenopathy or T3, T4
    – CT CAP w/ contrast or PET/CT
    – LN biopsy if LN >1.5 cm (or sig PET+)
•   Suspected sites of visceral involvement
    should be confirmed with appropriate
    imaging studies and/or histologic
    evaluation when possible                   Tsai et al, Arch Dermatol 142:577, 2006
TNMB Classification for Mycosis Fungoides and Sézary Syndrome,
NCI Workshop, 1978,

 T (Skin)                              N (Nodes)
  T1   Limited patch/plaque            N0    Lymph nodes clinically uninvolved
       (< 10% of total skin surface)
                                       N1    Lymph nodes clinically abnormal,
  T2   Generalized patch/plaque              histologically uninvolved
       (> 10% of total skin surface)
                                       N2*   Lymph nodes clinically uninvolved,
  T3   Tumors                                histologically involved
  T4   Generalized erythroderma        N3    Lymph nodes clinically abnormal,
                                             histologically involved


 M (Viscera)                           B (Blood)
  M0   No visceral involvement         B0    No circulating atypical (Sézary) cells
  M1   Visceral involvement            B1*   Circulating atypical (Sézary) cells



 *Modifications: old N2 deleted, redefined; B1 into B1, B2
Proposed Revisions to TNMB Classification and staging
for MF/SS, ISCL Consensus Document

T (Skin)                              N (Nodes)
 T1   Limited patch/plaque            N0   No clinically abnormal LNs
      (< 10% of total skin surface)
                                      N1   Clinically abnormal LNs; histopath Dutch
 T2   Generalized patch/plaque             Gr 1 or NCI LN0-2 (clone +/-)
      (> 10% of total skin surface)
                                      N2   Clinically abnormal LNs; histopath Dutch
 T3   Tumors                               Gr 2 or NCI LN 3 (clone +/-)
 T4   Generalized erythroderma        N3   Clinically abnormal LNs; histopath Dutch
                                           Gr 3-4 or NCI LN4 (clone +/-)
                                      Nx   Clinically abnormal LNs, no histo info


M (Viscera)                           B (Blood)
 M0   No visceral involvement         B0   No significant blood involvement
 M1   Visceral involvement            B1   Low blood tumor burden
                                      B2   High blood tumor burden
Clinical Staging System for Mycosis Fungoides
and Sézary Syndrome, NCI Workshop, 1978

   Clinical Stages                  TNM Classification*
          IA                 T1              N0              M0
          IB                 T2              N0              M0
          IIA              T1 - 2            N1              M0
          IIB                T3            N0 - 1            M0
         IIIA                T4              N0              M0
         IIIB                T4              N1              M0
         IVA               T1 - 4          N2 - 3            M0
         IVB               T1 - 4          N0 - 3            M1

 * The “B” classification did not alter clinical stage; but the
 system is undergoing modifications to reflect the adverse
 survival of B2 (similar to IVA)
Proposed Revisions to TNMB Classification and staging
for MF/SS, ISCL Consensus Document

 Clinical Stages            TNM Classification*
       IA           T1       N0           M0      B0-1
       IB           T2       N0           M0      B0-1
       IIA         T1 - 2    N1-2         M0      B0-1
       IIB          T3       N0-2         M0      B0-1
      IIIA          T4       N0-2         M0      B0
      IIIB          T4       N0-2         M0      B1
      IVA          T1 - 4    N0-3         M0      B0-2
      IVB          T1 - 4    N0-3         M1      B0-2
MF and SS, Disease-Specific Survival by Clinical Stage,
Stanford Update (n=525), Arch Dermatol 139:857-866, 2003
MF and SS, Risk of Disease Progression by T-Classification,
Stanford Update (n=525), Arch Dermatol 139:857-866, 2003
PC CD30+ Lymphoproliferative Disorders
Lymphomatoid papulosis === borderline === primary cutaneous ALCL


Lymphomatoid Papulosis (LyP):
   – Present alone, a/w Hodgkin’s, MF, or rarely other NHLs,
      or progress to ALCL
   – Self-healing, benign course
   – Histologic subtypes: A, B, C
      • Type C LyP is indistinguishable from ALCL, not a/w worse disease
        progression or survival
   – ALK1 or t(2;5) negative
PC CD30+ Lymphoproliferative Disorders

Lymphomatoid papulosis === borderline === primary cutaneous ALCL

PC CD30+ Anaplastic Large Cell Lymphoma
   – Primary presentation in skin w/o extracutaneous dz at diagnosis
     (need to distinguish from LC transformation of MF)
   – Solitary vs. regional vs. generalized nodules/tumors
      • No significant differences in survivals (Dutch Group)
      • ? worse outcome in pts with extensive regional involvement
   – Spontaneous regression observed in up to 25%
   – Extracutaneous disease development in 10-25%
   – Mostly ALK1 or t(2;5) negative
Non-MF/SS Cutaneous T-cell Lymphomas

Staging Evaluation
• Clinical history (B sx, etc)
• Physical examination
• Laboratory
   – CBC and chemistry survey including LDH
• Radiology
   – CT chest, abdomen & pelvis w/ contrast (include neck as needed)
   – PET/CT
• Bone marrow biopsy
• Other studies as indicated
PC CD30+ Lymphoproliferative Disorders
Survival Data

                            Overall Survival        Disease-specific Survival
              No. of
 Type
               Pts.
                               5-yr, 10-yr                  5-yr, 10-yr

 LyP           118             98%, 95%                    100%, 100%

 PC ALCL        79             83%, 78%                     96%, 96%

 PC ALCL
                11             76%, 76%                     91%, 91%
 + reg LN

Dutch Cutaneous Lymphoma Group, Blood 95:3653-61, 2000
(This study does not report the extensive regional limb presentation, introduced
in the Stanford review, J Am Acad Dermatol, 49:1049-1058, 2003 )
Subcutaneous Panniculitis-like T-cell Lymphoma

• Clinically and histologically heterogeneous group of cytotoxic T-
  cell lymphoma with preferential infiltration of subcutaneous tissue
• Tumor cells express CD3+, α/β+, CD4-, CD8+ T-cell phenotype, w/
  expression of cytotoxic molecules (TIA-1, granzyme B, perforin),
  CD30 & CD56 usu. negative; majority with clonal TCR
  rearrangement
• Often misdiagnosed as inflammatory panniculitis or infection
• Solitary/regional or multiple anatomic site presentation with
  variable degrees of cutaneous necrosis
• Can have a period of indolent course w/ recurrent subcutaneous
  nodules w/o extracutaneous disease or hemophagocytic
  syndrome; subset w/ aggressive clinical course especially when
  a/w hemophagocytic syndrome
Extranodal NK/T-cell Lymphoma, Nasal Type

• Includes previously designated “angiocentric lymphoma”
• Atypical cells express CD2, CD56, cytotoxic proteins, most are
  surface CD3- and cytoplasmic CD3+ and have germline TCR;
  subset of true T-cell origin may have TCR rearrangement
• Extranodal sites: nose, palate, upper airway, GI tract, skin
• Aggressive clinical course with poor response to therapy and
  short survival; subset with better prognosis
   – Clinical variant includes Hydroa vacciniforme-like presentation
Cutaneous NK/T-cell Lymphoma, nasal-type
Stanford Review of 33 Pts: J Clin Oncol 19:2179-88, 2001

• Primary presentation in the skin
• Age range 14-97, median age 50
• Solitary/localized (11/33, 33%) or multiple skin sites
• Extracutaneous sites (11/33, 33%):
   – LN (12%), BM (27%), CNS, liver, spleen, adrenal
• Overall aggressive course with median survival of 15 mo
• Patients with presentation limited to skin and/or co-expression of
  CD56/CD30 with more favorable outcome
• EBV/MDR does not predict worse outcome
Adult T-cell Leukemia/Lymphoma
• T-cell neoplasm etiologically a/w HTLV-1
• Neoplastic T-cells are CD3+, CD4+, CD8-, CD25
• Endemic in Japan, the Caribbean, S Americas, Central Africa
• ATLL develop in 1-5% of seropositive individuals after long years
  of viral persistence
• Most present as acute dz w/ leukemia, LN+, organomegaly, ↑Ca++,
  50% w/ skin lesions, most commonly nodules or tumors,
  generalized papules or plaques
   – Chronic and smoldering variants frequently present w/ skin lesions
     that resemble MF (lack circulating neoplastic T-cells), transformation
     into acute dz may occur; demonstration of clonally integrated HTLV-
     1 genes differentiates from MF
• Therapy is tailored for acuity/severity of disease
Cutaneous T- and NK/T-cell Lymphomas
New WHO-EORTC Classification

Mycosis fungoides and variants/subtypes

Sézary syndrome

PC CD30+ lymphoproliferative disorders

Subcutaneous panniculitis-like T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Adult T-cell leukemia/lymphoma
PC peripheral T-cell lymphoma, unspecified
   • Aggressive epidermotropic CD8+ T-cell lymphoma
   • Cutaneous γ/δ T-cell lymphoma
   • PC CD4+ sm/med-sized pleomorphic T-cell lymphoma
   • PTCL, other
    Aggressive Epidermotropic CD8+ T-cell Lymphoma
•   Proliferation of epidermotropic CD8+
    cytotoxic T-cells and an aggressive
    clinical behavior
•   Localized or generalized eruptive
    papules, nodules, and tumors
    showing central ulceration and
    necrosis
•   Generalized hyperkeratotic patches
    and plaques
•   Extracutaneous sites are lung, testis,
    CNS, oral mucosa; LNs often spared
•   Combined modality regimens,
    systemic single or multi agent
    chemotherapies
Cutaneous γ/δ T-cell Lymphoma
• Clonal proliferation of mature, activated γ/δ T-cells w/ a cytotoxic
  phenotype
   – CD2+, CD3+, betaF1-, CD5-, CD56+, cytotoxic proteins
   – Generally CD4-, CD8-, EBV-
   – Epidermotropic, dermal, and/or subcut. histologic patterns
• Generalized plaques and/or ulceronecrotic nodules or tumors
   –   Extremities often involved
   –   Mucosal and other extranodal sites frequently involved
   –   Involvement of LNs, spleen or BM is uncommon
   –   Hemophagocytic syndrome (HPS) may occur
• Tendency for aggressive clinical course (esp. w/ HPS and/or
  subcutaneous histology)
• Primary treatment is systemic chemotherapy +/- high-dose therapy
  with SC rescue
PC Peripheral T-cell Lymphoma, Other

• CD4+ sm/med-sized pleomorphic T-cell lymphoma
   –   Without h/o patches and plaques typical of MF
   –   Solitary or multiple plaque, nodules, or tumors
   –   Most commonly on head/neck, trunk
   –   Tendency for indolent course
• CD30- large cell lymphoma (PTCL, unspecified)
   – Solitary/localized or generalized nodules or tumors
   – CD4+, CD30- large cells > 30% of tumor cells
   – Variable clinical course
Cutaneous T-cell Lymphoma
Mycosis Fungoides & Sézary Syndrome

Diagnosis
• Routine histology
   – >1 punch biopsies, off topical therapy
• Immunophenotyping
   – immunohistochemistry, flow cytometry
• Gene rearrangement (clonality)
   – PCR methods
• Clinical correlation***
Algorithm for the Diagnosis of Early MF*

                               Criteria                           Major        Minor
                                                                (2 Points)   (1 Point)
CLINICAL
Persistent and/or progressive patches and plaques plus            Any 2        Any 1
     1. Non-sun exposed location
     2. Size/shape variation
     3. Poikiloderma
HISTOPATHOLOGICAL
Superficial lymphoid infiltrate plus                               Both        Either
     1. Epidermotropism
     2. Atypia
MOLECULAR/ BIOLOGICAL
Clonal TCR gene rearrangement                                                 Present
IMMUNOPATHOLOGICAL
     1. CD2,3,5 <50%                                                           Any 1
     2. CD7< 10%
     3. Epidermal discordance

* ISCL Concensus Report, J Am Acad Dermatol 2005; 54: 1053-63
Non-MF Cutaneous T-cell Lymphomas

Diagnosis
• Clinical suspicion
• Incisional (large and deep) or excisional biopsy
  == NO small punch or shave biopsy
• Important role of immunohistochemistry and/or molecular studies
Handouts for Forum 506 available 8/1/06 at

cutaneouslymphoma.stanford.edu

or email younkim@stanford.edu