mycosis fungoides sheikha mycosis fungoides. professor anwar sheikha md, frcp, frcpath., fcap,...
TRANSCRIPT
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES
Professor
Anwar SheikhaAnwar SheikhaMD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP
Senior Consultant Clinical & Lab. Hematologist
Clinical Professor of HematologyUniversity of Mississippi Medical Center, Jackson,
Mississippi
Professor of Hematology, University of Salahaddin, Erbil, Kurdistan, IRAQ
Owner & C.E.O., Raziana Company for Health Services, Hawler, IRAQ
MYCOSIS FUNGOIDES SHEIKHA
MF is a cutaneous lymphoma of mature CD4+ T cells
The commonest cutaneous T-cell lymphoma
It has unique clinical & histologic features
Not all cutaneous T-cell lymphomas are MF
MYCOSIS FUNGOIDES
SEZARY SYNDROME
MF/SZ
MYCOSIS FUNGOIDES SHEIKHA
Professor Lennert, Keil Classification
MYCOSIS FUNGOIDES SHEIKHA
W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Classical Hodgkin Lymphoma
B T & NK
HD
PrecursorB-cell neoplasms
Mature (Peripheral)B-cell neoplasms
PrecursorT-cell neoplasms
Mature (Peripheral)T-cell neoplasms
NHL
*
W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS
T & NK
Mature (Peripheral)T-cell neoplasms
NHL*T-cell Prolymphocytic Leukemia*T-cell Granular Lymphocytic Leukemia
*Aggressive NK-cell Leukemia
*Adult T-cell Leukemia/Lymphoma (HTLV1)
*Extranodal NK/T-cell Lymphoma. Nasal type
*Entropathy-type T-cell Lymphoma*Hepatosplenic γδ T-cell Lymphoma
*Subcutaneous Panniculitis-like T Lymphoma
*Mycosis Fungoides /Sézary Syndrome *Anaplastic Large-cell Lymphoma/T/null, skin type
*Peripheral T-cell Lymphoma, not otherwise characterized
*Angioimmunoblastic T-cell Lymphoma
*Anaplastic Large-cell Lymphoma/T/null, systemic type
*
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
Incidence: 3 per million (0.29 per 100,000 population in USA)
2% of all new cases of NHL
Age: Older adults (55 to 60)
Male/Female: 2/1
PATCH
STAGE PLAQUESTAGE
TUMORSTAGE
ERYTHRODERMA
“SEZARY”
Epidermo-
tropism
Cerebriform
“Sezary” Cells
MYCOSIS FUNGOIDES SHEIKHA
Patch Plaque TumorStage
SézarySyndrome
MF patches are usually distributed in sun-shielded areas such as those covered by a bathing suit or intertriginous regions.
Various Cutaneous Manifestations of Mycosis Fungoides
MYCOSIS FUNGOIDES SHEIKHA
The cardinal features of MF is infiltration of epidermis and then dermis by Atypical Cerebriform Lymphoid Cells
EPIDERMOTROPIC
Girardi M et al. N Engl J Med 2004;350:1978-1988
Mycosis Fungoides: A Cancer of Skin-Homing T Cells
Multiple discrete &
confluent plaques of
cutaneous T-cell lymphoma
“MF”
Multiple plaques of cutaneous
T-cell lymphoma with
tumor formation
“MF”
1. PATCH STAGE
Mild epidermal hyperplasia withperivascular or band-like infiltrateof small- to medium-sized atypicallymphocytes with cerebriform nuclearconvolution.
EPIDERMOTROPISM:Cerebriform lymphocytes exhibitepidermotropism and are arrangedalong the dermal-epidermal junctionin a single-file pattern or scattered in the epidermis.
Pautrier’s microabscesses are smallintra-epidermal collections of cerebriform lymphocytes & are pathognomonic forMF. They might not be present in earlystages of MF
MF
PA
TC
HE
S
Eczematoid
2. PLAQUE STAGE:
The density of the neoplastic cells within dermis increases
Exaggerated epidermotropism
Psoriasiform
2. PLAQUE STAGE:
The density of the neoplastic cells within dermis increases
Exaggerated epidermotropism
Psoriasiform
Plaque Stage: A broad band-like cellular infiltrate in the upper dermis
Pautrier
3. TUMOR STAGE:
VERTICAL GROWTH
Very dense dermal infiltrateinvolving the full breadth ofthe dermis & extending tothe subcutaneous fat.
Epidermotropism diminishes
Tumors could get infected sepsis death
de novo tumor
“d’emblee”دومهل
ERYTHRODERMA
Pathology similar to Patch stagebut infiltrate is more sparse
Generalized erythroderma withSézary cells “with cerebriformnuclei” in blood of >1,000/uL
Sézary Syndrome
↑CD4 to CD8 ratio >10:1
T-cell Receptor generearrangement
Intensely symptomaticfrom pruritus & scaling
Usually have lymphadenitis
Generalizederythroderma
Lympha-denopathy
Sézary cells
Sézary Syndrome =
MYCOSIS FUNGOIDES SHEIKHA
Pautrier Abscesses
MYCOSIS FUNGOIDES SHEIKHA
LYMPH NODE INVOLVEMENT IN MF or SZS
DERMATOPATHIC LYMPHADENITIS = DL
CATEGORY I“LN0-LN2”
CATEGORY II“LN3”
CATEGORY III“LN4”
LN0 = DL/ No atypical LC
LN1 = Scattered atypical cerebriform LC (not in clusters) ± DL
LN2 = Small clusters < 6 cells ± DL
Clusters of 10 or moreatypical LC confined tothe paracortex ± DL
Partial or completeeffacement of LNarchitecture bycytologically atypical lymphocyte
MYCOSIS FUNGOIDES SHEIKHA
IMMUNOPHENOTYPE in MF/SZS
CD2+
CD3+
CD4+
CD5+
CD25 -/+
CD7-
CD30-
Molecular Diagnosis:PCR of T-cell Receptor γrearrangement, especially
in early patch stages
Cell of Origin:CD4+ T lymphocyte with skin
homing “epidermotropic” properties
MYCOSIS FUNGOIDES SHEIKHA
CLINICAL PRESENTATION OF MF
MF often has a long natural history
Median duration from onset to diagnosis may be 5 years or more
Usually starts with scaly skin lesions that wax & wane over years
Biopsy at this stage is usually non-diagnostic
Patient may respond at this stage to topical steroid
Repeated biopsy is warranted if MF is suspected and biopsy is negative
MYCOSIS FUNGOIDES SHEIKHA
CLINICAL PRESENTATION OF MF
30% Limited patchor plaque stage<10% BSA
T1
35-40% Generalized patchor plaque stage>10% BSA
T2 15-20% Tumorous stage<10% BSA
T315% Erythro-derma
T4
PRURITUSCommonest symptom of MF
Only 15% of MF patients show extracutaneous disease.Lymph nodes; Visceral disease, etc
MYCOSIS FUNGOIDES SHEIKHA
OTHER FEATURES OF MF
Skin Hair Follicles could be extensively infiltrated. Mucin might be deposited Follicular MF
Pagetoid reticulosis is a verrucous variant of MF Affecting acral sites like hands & feet. Extreme atypical LC epidermotropism verrucae
Granulomatous slack skin pendulous folds of slack or lax skin “macrophage-mediated destruction of dermal elastic fibers”
Many MF have only skin problems. 15% have extracutaneous disease;LN, Visceral sites “Lung, Oral cavity, CNS, etc” could be affected.
Various Cutaneous Manifestations of Mycosis Fungoides
MYCOSIS FUNGOIDES SHEIKHA
STAGING OF MF
MYCOSIS FUNGOIDES SHEIKHAT (SKIN)
T1 Limited patch/plaque
(<10% total skin surface)
T2 Generalized patch/plaque
(>10% total skin surface)
T3 Tumors
T4 Generalized Erythroderma
N (LYMPH NODES)
N0 LN Clinically uninvolved
N1 Enlarged; histologically uninvolved (reactive & dermatopathic)
N2 LN Clinically uninvolved;
histologically involved
N3 LN enlarged & involved
M (VISCERA)
M0 No Visceral
involvement
M1 Visceral
involvement
B (BLOOD)
B0 No Sézary cells
(<5% of LC)
B1 Circulating
Sézary cells
(>5% of LC)
Tumor-Node-
Metastasis-Blood
ClassificationForMF
MYCOSIS FUNGOIDES SHEIKHA
Clinical
stagesT N M
IA T1 N0 M0
IB T2 NO M0
IIA T1-2 N1 M0
IIB T3 tumor N0-1 M0
IIIA Erythroderma T4 N0 M0
IIIB Erythroderma T4 N1 M0
IVA T1-4 N2-3 histology M0
IVB T1-4 N0-3 M1
CLINICAL STAGING SYSTEM FOR MF
B CLASSIFICATION (SEZARY CELLS) DOES NOT ALTER CLINICAL STAGE
MYCOSIS FUNGOIDES SHEIKHA
T (SKIN)
T1 Limited patch/plaque
(<10% total skin surface)
T2 Generalized patch/plaque
(>10% total skin surface)
T3 Tumors
T4 Generalized Erythroderma
N (LYMPH NODES)
N0 LN Clinically uninvolved
N1 Enlarged; histologically uninvolved (reactive & dermatopathic)
N2 LN Clinically uninvolved;
histologically involved
N3 LN enlarged & involved
M (VISCERA)
M0 No Visceral involvement
M1 Visceral involvement
B (BLOOD)
B0 No Sezary cells
(<5% of LC)
B1 Circulating cells
(>5% of LC)
Clinical stages T N M
IA T1 N0 M0
IB T2 NO 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
Tumor-Node-Metastasis-Blood & Clinical Staging Classification
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
TOPICALCHEMO-THERAPY
TREATMENT OF MF
TOPICAL NITROGEN MUSTARD “MECHLORETHAMINE"Effective
Mechanism ??
OINTMENT
AQUEOUSSOLUTION
10 to
20
mg
Per 1
00
cc
=
Choice of aqueous or ointment depends on convenience, preference & costHypersensitivity is 30% with Aqueous solution & < 5% with ointment
MYCOSIS FUNGOIDES SHEIKHA
Topical N2-Mustard is applied locally or to the entire skin at least dailyduring the clearing phase.
After few weeks treatment may be applied to the affected region.
N2-Mustard may only be applied to the affected anatomical site if the disease is really limited.
Treatment is continued on daily basis until the lesions are cleared (6 months+) 3 to 6 months of maintenance therapy
If response is slow; increase N2-Mustard concentration or frequency of application
CR rate for limited patch or plaque stage “T1” is 70% to 80%
The median time to skin clearance is 6 to 8 months
20% to 25% have durableCR of > 10 years
Local Radiation to Refractory local lesions
Half will relapse after discontinuation of R/ but respond again
MYCOSIS FUNGOIDES SHEIKHA
TOPICALCHEMO-THERAPY
TREATMENT OF MF
TOPICAL Carmustine “BCNU"
Similar efficacy to N2- Mustard but it could be absorbed & cause myelosuppression,thus limiting its long-term use.
BCNU use could cause telangiectasias in areas exposed to the drug
MYCOSIS FUNGOIDES SHEIKHA
PHOTO-THERAPY
TREATMENT OF MF
Ultraviolet Light (UV) UVA or UVB wavelength ± Psoralen = PUVAPsoralen is a photosensitizing agent
The long-wave UVA has greater dermal penetration power
For early Limited disease UVB alone or Home UV phototherapy (UVA & UVB) could be effective
PUVA is the most commonly used form of therapy for MF & SZSIt is effective in Psoriasis but has also been found to be effective in MF
PUVA is used 2-3 times/week during the clearance phase ( >6 months)Reduce frequency in maintenance phase. For recurrence ↑ frequency again
Complete clearance rate with PUVA is 50% to 90% for patch & plaque stageLess response for erythrodermic or tumor stage
MYCOSIS FUNGOIDES SHEIKHA
PUVACOMPLICATIONS
ACUTE:
NauseaPhototoxic reactions such as erythroderma, blistering & dryness
Shield eyes & skin from sun for 24 hrs after Psoralen ingestion
LONG TERM:
Cataract (use UVA opaque goggles during therapy)Secondary cutaneous malignancy
MYCOSIS FUNGOIDES SHEIKHA
TOPICALRETINOIDS
Bexarotene“Targretin”
1% Gel
Overall Response Rate is 63%Complete Response rate is 21%
Because of the irritant effect, it is only used for discrete patch or plaque stageNot applicable in generalized disease
Apply thin over the lesions twice dailyIrritation is a rule. Withhold for few weeks if erythema
MYCOSIS FUNGOIDES SHEIKHA
RADIATIONTHERAPY
TREATMENT OF MF
MF is an exquisitely radiosensitive neoplasmIrradiation may be exploited in several ways
Individual plaques or tumors of MF may be treated to totaldoses of 15 to 25 Gy in 1 to 3 weeks, with a high likelihoodof achieving long-term local control.
For the unusual patient with with unilesional or localized MF, local electron beam therapy achieves the most efficient & complete clearance of the disease
Depth of penetration of electrons is controllable; this is of major advantage in MF
Depth of R/ with TSEBT is better than N2-Mustard or PUVA
MYCOSIS FUNGOIDES SHEIKHA
TOTAL SKIN ELECTRON BEAM THERAPY“Stanford Technique”
OVERALL RESPONSE RATE 100%COMPLETE RESPONSE RATE 98%
50% OF T1 & 25% OF T2 ARE FREE OF DISEASE 5 YEARS AFTER A
SINGLE COURSE
A full cycle takes 2 days2 Gy is given per cycle
Total dose of around 36 Gy is given over 10 weeks;
Give a week rest in middleto give relief from erythema
Indications:
Very thick plaquesRecent rapid progressionOther local therapy are ineffective
Local N2-Mustardis indicated for 6
months after TSEBT
Complications:
ErythemaDry desquamation
AlopeciaNail loss
Sweating problems
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
SYSTEMICCHEMO-
THERAPY
TREATMENT OF MF
Only for Extracutaneous MF80% to 100% Complete or Partial ResponseDuration of Response is usually < 1 year
CHOP COP CAVE COMP
MYCOSIS FUNGOIDES SHEIKHA
OTHERTREATMENTS
TREATMENT OF MF
ExtracorporealPhotopheresis
Interferon-αSystemicRetinoids
RecombinantFusion Proteins
IL-2-diphtheria toxin (Ontak; denileukin diftitox)For IL-2 receptor “CD25+” MF
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
OUTCOME
STAGE IA (Limited Patch or Plaque, T1) Disease
Excellent Prognosis with conventional TreatmentLife Expectancy = Age Matched PopulationOnly 9% progress to more advanced stages
Aggressive Therapy has no Survival AdvantageDo not over treat
MYCOSIS FUNGOIDES SHEIKHA
OUTCOME
STAGE IB/IIA (Generalized Patch or Plaque, T2) Disease
Median Survival of 11 years25% MR from MF
MYCOSIS FUNGOIDES SHEIKHA
OUTCOME
STAGE IIB (Tumorous) Disease
Median Survival of 3.2 yearsMajority die of MF
MYCOSIS FUNGOIDES SHEIKHA
OUTCOME
STAGE III (Erythrodermic, T4) Disease
Total Skin Electron Beam Therapy is not recommended
Survival is variable
MYCOSIS FUNGOIDES SHEIKHA
OUTCOME
STAGE IV (Extracutaneous) Disease
Poor PrognosisMedian Survival 13 months
MYCOSIS FUNGOIDES SHEIKHA
REVISON
Various Cutaneous Manifestations of Mycosis Fungoides
Panel A shows patch-or-plaque MF affecting the lower trunk. The patches are thin, slightly scaly, erythematous lesions typically greater than 4 cm in diameter and distributed in sun-shielded areas such as those covered by a bathing suit or intertriginous regions. Plaques are thicker than patches.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel B shows pagetoid reticulosis, a variant of mycosis fungoides that typically consists of a single patch or plaque located in an acral area.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel C shows syringotropic mycosis fungoides, which is manifested as papules 1 to 3 mm in diameter distributed in the eccrine ducts, indicating the propensity of lymphoma cells to accumulate in these locations.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel D shows follicular mycosis fungoides, in which lesions characterized by alopecia develop. In a similar variant, there is mucin deposition in the follicles.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel E shows hypopigmented mycosis fungoides. This variant is more noticeable in persons with dark pigmentation and may be more common in childhood and adolescence than in adulthood. Hypopigmentation to full depigmentation occurs in patches.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel F shows erythrodermic mycosis fungoides. This variant may evolve from patch-or-plaque mycosis fungoides and eventually involve more than 80 percent of the body-surface area.
It may also arise spontaneously, as in the Sézary syndrome.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel G shows the Sézary syndrome. In its most florid form, the diffuse infiltration of the skin may produce the exaggerated facial lines, resulting in "leonine facies."
The Sézary syndrome is also associated with atypical lymphocytes on the blood smear.
Various Cutaneous Manifestations of Mycosis Fungoides
Panel H shows a mycosis fungoides tumor. Such tumors define the T3 stage of disease and may arise at the site of plaques or appear on their own, without being preceded by a patch-or-plaque lesion. The vertical growth phase is accelerated, and tumors tend to appear more quickly than plaques. Tumors not characterized by epidermotropism or previous mycosis fungoides are sometimes called "non–mycosis fungoides cutaneous T-cell lymphoma
Various Cutaneous Manifestations of Mycosis Fungoides
Let me now examine you
MYCOSIS FUNGOIDES SHEIKHA
THANK YOU
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
Girardi M et al. N Engl J Med 2004;350:1978-1988
Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome
MYCOSIS FUNGOIDES SHEIKHA
Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
ATCLL
Blood of a Cutaneous T-cell Lymphoma Patient
showing Sézary cells
Pautrier microabscess
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
Figure 2. Mycosis Fungoides: A Cancer of Skin-Homing T Cells. In cutaneous T-cell lymphoma, cells home to the skin by virtue of interactions with dermal capillary endothelial cells. Circulating lymphoma cells bearing cutaneous lymphocyte antigen (CLA) roll along endothelial cells expressing E-selectin. Chemokine receptors (e.g., CC chemokine receptor 4 [CCR4]) on the malignant T cells recognize chemokines (e.g., CC chemokine ligand 17 [CCL17]) that have emanated from the epidermis and bound to the luminal side of endothelial cells, greatly facilitating the binding of leukocyte-function–associated antigen type 1 on the lymphoma cells to intercellular adhesion molecule 1 on the endothelial cells and subsequent extravasation into the dermis. From there, the lymphoma cells often display an affinity for epidermal cells and cluster around Langerhans' cells, forming Pautrier's microabscesses, which can be observed on histologic examination. This process is principally guided by the interactions of lymphoma-cell integrin E 7, CCR4, and the CD4 T-cell receptor complex with E-cadherin, CCL22, and major-
histocompatibility-complex class II (MHC-II) molecules, respectively. TCR denotes T-cell receptor.
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
WHAT TO REMEMBER ABOUT MF
It is an indolent troublesome diseaseFlat patches, thin plaques, deep tumors & ErythrodermaCerebriform cellsEpidermotropismThe patient has to live with it in the majority of cases
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
MYCOSIS FUNGOIDES SHEIKHA
TREATMENT OF MF
SYMPTOMATIC:
Pruritus & xerosis could be severeR/ Aggressive emolliation, topical steroid & oral antipruritics Dermatologists
MF TREATMENT:
TOPICALCHEMO-THERAPY
PHOTO-THERAPY
TOPICALRETINOIDS
RADIATIONTHERAPY
SYSTEMICCHEMO-THERAPY
Extracorporeal PhotopheresisInterferon –αRetinoidsRecombinant Fusion ProteinsCombined Modality Therapy
Mycosis fungoides
Mycosis fungoides lymph node involvement
MYCOSIS FUNGOIDES SHEIKHA
Plaque Stage: A broad band-like cellular infiltrate in the upper dermis
MYCOSIS FUNGOIDES SHEIKHA
Patch Plaque
TumorStage
SézarySyndrome