Transcript Z_Dermatology_Mycosis_Fungoides

MYCOSIS FUNGOIDES
SHEIKHA
MYCOSIS
FUNGOIDES
MYCOSIS FUNGOIDES
SHEIKHA
Dermatology
is
NOTHING
MYCOSIS FUNGOIDES
SHEIKHA
BUT
An External
Hematology
MYCOSIS FUNGOIDES
SHEIKHA
Dermatology
is
Nothing …
BUT
AN EXTERNAL
HEMATOLOGY
New England Journal of Medicine
MYCOSIS FUNGOIDES
SHEIKHA
Hematology
is
Nothing
BUT
AN INTERNAL
DERMATOLOGY
DERMATOLOGY
HEMATOLOGY
The two sides of the same coin
Professor
Anwar Sheikha
MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP
Senior Consultant Clinical & Lab. Hematologist
Clinical Professor of Hematology
University 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
‫كومبانياى ﺮﺍﺰﯿﺎﻨﻪ پروژﻩى‬
‫نه خوشخانه و شيرپه نجه خانه ى‬
‫ميديا دروست دەكات‬
‫ﭘﺮﻮﮊﻩﻜﻪ ﺑﺮﯾﺘﯾﻪ ﻠﻪ ‪ ۲۰۰‬ﮊﻮﺮﻯ ﻧﻪﺧﻮﺵ ﻮ ﻛﻮﻣﻪﻠﮕﺎﻯ ﻛﻠﯾﻧﯾﻛﻮ ﻣﺎﻠﻰ ﭙﺰﯾﺷﮑﺎﻥ‬
“RAZIANA COMPANY ”
MEDYA MEDICAL & CANCER CENTER
MEDIA MEDICAL &
CANCER CENTER
A 200 BED HOSPITAL, MEDICAL OFFICE BUILDINGS
& A RESIDENCE VILLAGE AT A COST OF ~ $50 MILLION
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
SÉZARY
SYNDROME
MF/SZ
LYMPHOMA IS THE MOST CONFUSING PART OF MEDICINE
MYCOSIS FUNGOIDES
SHEIKHA
Professor Lennert,
Keil Classification
MYCOSIS FUNGOIDES
SHEIKHA
W.H.O.
CLASSIFICATION OF LYMPHOID NEOPLASMS
B
NHL
T
&
NK
Precursor
Precursor
B-cell neoplasms
T-cell neoplasms
Mature (Peripheral)
B-cell neoplasms
Mature (Peripheral)
T-cell neoplasms
*
HD
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Classical Hodgkin Lymphoma
W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS
*T-cell Prolymphocytic Leukemia
*T-cell Granular Lymphocytic Leukemia
*Aggressive NK-cell Leukemia
T
&
NK
NHL
*Adult T-cell Leukemia/Lymphoma (HTLV1)
*Extranodal NK/T-cell Lymphoma. Nasal type
Mature (Peripheral)
T-cell neoplasms
*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
Epidermo
tropism
PLAQUE
STAGE
ERYTHRODERMA
“SÉZARY”
TUMOR
STAGE
Cerebriform
“Sézary”
Cells
MYCOSIS FUNGOIDES
Patch
SHEIKHA
Plaque
MF patches are usually distributed in sunshielded areas such as those covered by a
bathing suit or intertriginous regions.
Tumor
Stage
Sézary
Syndrome
Various Cutaneous Manifestations of Mycosis Fungoides
MYCOSIS FUNGOIDES
SHEIKHA
EPIDERMOTROPIC
The cardinal features of MF is infiltration of epidermis and then dermis
by Atypical Cerebriform Lymphoid Cells
Mycosis Fungoides: A Cancer of Skin-Homing T Cells
Girardi M et al. N Engl J Med 2004;350:1978-1988
MYCOSIS FUNGOIDES
SHEIKHA
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 with
perivascular or band-like infiltrate
of small- to medium-sized atypical
lymphocytes with cerebriform nuclear
convolution.
MF PATCHES
EPIDERMOTROPISM:
Cerebriform lymphocytes exhibit
epidermotropism and are arranged
along the dermal-epidermal junction
in a single-file pattern or scattered
in the epidermis.
Pautrier’s microabscesses are small
intra-epidermal collections of cerebriform
lymphocytes & are pathognomonic for
MF. They might not be present in early
stages of MF
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
Plaque Stage: A broad band-like
cellular infiltrate in the upper dermis
Pautrier
Psoriasiform
3. TUMOR STAGE:
VERTICAL GROWTH
Very dense dermal infiltrate
involving the full breadth of
the dermis & extending to
the subcutaneous fat.
Epidermotropism diminishes
de novo tumor
“d’emblee”
‫ﺩﻮﻤﻪﻞ‬
Tumors could get infected  sepsis  death
ERYTHRODERMA
Pathology similar to Patch stage
but infiltrate is more sparse
Generalized erythroderma with
Sézary cells “with cerebriform
nuclei” in blood of >1,000/uL 
Sézary Syndrome
↑CD4 to CD8 ratio >10:1
T-cell Receptor gene
rearrangement
Intensely symptomatic
from pruritus & scaling
Usually have lymphadenitis
Sézary Syndrome =
Generalized
erythroderma
Sézary
cells
Lymphadenopathy
MYCOSIS FUNGOIDES
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Pautrier Abscesses
MYCOSIS FUNGOIDES
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LYMPH NODE INVOLVEMENT IN MF or SZS
DERMATOPATHIC LYMPHADENITIS = DL
CATEGORY I
“LN0-LN2”
LN0 = DL/ No atypical LC
LN1 = Scattered atypical
cerebriform LC (not
in clusters) ± DL
LN2 = Small clusters < 6
cells ± DL
CATEGORY II
“LN3”
CATEGORY III
“LN4”
Clusters of 10 or more Partial or complete
atypical LC confined to effacement of LN
the paracortex ± DL
architecture by
cytologically
atypical lymphocyte
MYCOSIS FUNGOIDES
SHEIKHA
IMMUNOPHENOTYPE in MF/SZS
CD2+
CD3+
CD30-
CD4+
CD5+
CD25
-/+
Molecular Diagnosis:
PCR of T-cell Receptor γ
rearrangement, especially
in early patch stages
Cell of Origin:
CD4+ T lymphocyte with skin
homing “epidermotropic” properties
CD7-
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 patch
or plaque stage
<10% BSA
T1
35-40%
Generalized patch
or plaque stage
>10% BSA
T2
15-20%
Tumorous stage
<10% BSA
PRURITUS
Commonest symptom of MF
Only 15% of MF patients show extracutaneous disease.
Lymph nodes; Visceral disease, etc
T3
15%
Erythroderma
T4
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
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STAGING OF MF
MYCOSIS FUNGOIDES
T
T1
T2
TumorNodeMetastasisBlood
Classification
For
MF
SHEIKHA
(SKIN)
Limited patch/plaque
(<10% total skin surface)
Generalized patch/plaque
(>10% total skin surface)
T3 Tumors
T4 Generalized Erythroderma
N
N0
N1
(LYMPH NODES)
N2
LN Clinically uninvolved;
histologically involved
N3
LN enlarged & involved
LN Clinically uninvolved
Enlarged; histologically
uninvolved (reactive &
dermatopathic)
M
M0
(VISCERA)
M1
Visceral
involvement
B
B0
(BLOOD)
No Visceral
involvement
No Sézary cells
(<5% of LC)
B1
Circulating
Sézary cells
(>5% of LC)
MYCOSIS FUNGOIDES
SHEIKHA
CLINICAL STAGING SYSTEM FOR MF
Clinical
stages
T
N
M
IA
IB
IIA
IIB
T1
T2
T1-2
T3 tumor
T4
T4
T1-4
T1-4
N0
NO
N1
N0-1
N0
N1
N2-3 histology
N0-3
M0
M0
M0
M0
M0
M0
M0
M1
IIIA Erythroderma
IIIB Erythroderma
IVA
IVB
B CLASSIFICATION (SEZARY CELLS) DOES NOT ALTER CLINICAL STAGE
MYCOSIS FUNGOIDES
T
T1
T2
(SKIN)
Limited patch/plaque
(<10% total skin surface)
Generalized patch/plaque
(>10% total skin surface)
T3 Tumors
T4 Generalized Erythroderma
N
N0
N1
(LYMPH NODES)
LN Clinically uninvolved
Enlarged; histologically
uninvolved (reactive &
dermatopathic)
N2
LN Clinically uninvolved;
histologically involved
N3
LN enlarged & involved
SHEIKHA
M
M0
(VISCERA)
M1
Visceral
involvement
No Visceral
involvement
B
B0
(BLOOD)
B1
Circulating cells
(>5% of LC)
No Sezary 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
Dear Professor Hoppe,
I am writing on behalf of a strong-willed 32 year old Iraqi Kurdish patient with the
diagnosis of mycosis fungoides, involving almost 20% of her body surface area.
Patient gives three years history of scaly skin lesions, not responding to topical
dermatological treatment. Recent histology sections showed the diagnosis
of early stage mycosis fungoides.
Patient desires consultation from Stanford, specifically asking for yourself.
I truly appreciate having an appointment for January 2007 with a formal
letter indicating the detail of the visit and the cost associated with the treatment.
After having the appointment letter from your hospital, we usually need
few months to process the visa to USA.
Looking forward to hearing from you.
Professor Anwar Sheikha, MD, FRCP, FRCPath.
MYCOSIS FUNGOIDES
SHEIKHA
Dear Professor Sheikha,
Thank you for your inquiry regarding possible consultation and treatment for
mycosis fungoides. We would be happy to see your patient at Stanford.
We have a comprehensive multi-disciplinary cutaneous lymphoma clinic that
includes dermatologists (Dr. Y. Kim is the Director), radiation oncologists,
medical oncologists, and dermatopathologists.
Our preference is to see all new patients in this clinic before making specific
recommendations for therapy. We employ a variety of topical and systemic
therapies for management and one of our major treatment programs is with
total skin irradiation.
Considering the special circumstances for this patient, to facilitate her visit
and treatment, it would probably be best while we are waiting for visa
clearance, etc. to be able to review the biopsy material. It might be simplest
if you request the slides and then forward them to me (R. Hoppe,
Department of Radiation Oncology, Room CC-G224, 875 Blake Wilbur Drive,
Stanford CA 94305). I will then obtain review from Stanford Pathology.
MYCOSIS FUNGOIDES
SHEIKHA
Assuming we confirm the diagnosis, we would be able to save some time once the
patient arrives. It is possible we may recommend treatment other than irradiation
(e.g., phototherapy or topical agents) that does not require staying at Stanford.
If that is the case, the expense would probably not be greater than several hundred
to a few thousand dollars, depending on other examinations (e.g., radiology, etc.)
that we may recommend. If we recommend a course of total skin irradiation,
the "list price" would total ~$76,000.
Our clinic will be meeting in January on January 11, 25, and 26 and we could
arrange an appointment for any of those dates.
In addition, I have taken the liberty of contacting Barbara Ralston in our Office of
Special Patient Services to facilitate these arrangements.
If you have any other questions, please feel free to contact me.
Sincerely,
Rich Hoppe
Chair, Radiation Oncology
MYCOSIS FUNGOIDES
SHEIKHA
TREATMENT OF MF
TOPICAL
CHEMOTHERAPY
TOPICAL NITROGEN MUSTARD “MECHLORETHAMINE"
Mechanism ??
10 to 20 mg
Per 100 cc
=
Effective
Choice of aqueous or ointment depends on convenience, preference & cost
Hypersensitivity is 30% with Aqueous solution & < 5% with ointment
MYCOSIS FUNGOIDES
SHEIKHA
Topical N2-Mustard is applied locally or to the entire skin at least daily
during 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
Half will relapse after discontinuation of R/ but respond again
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 durable
CR of > 10 years
Local Radiation to
Refractory local lesions
MYCOSIS FUNGOIDES
SHEIKHA
TREATMENT OF MF
TOPICAL
CHEMOTHERAPY
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
PHOTOTHERAPY
SHEIKHA
TREATMENT OF MF
Ultraviolet Light (UV)  UVA or UVB wavelength ± Psoralen =
Psoralen is a photosensitizing agent
PUVA
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 & SZS
It 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 stage
Less response for erythrodermic or tumor stage
MYCOSIS FUNGOIDES
SHEIKHA
PUVA
COMPLICATIONS
ACUTE:
Nausea
Phototoxic 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
TOPICAL
RETINOIDS
SHEIKHA
Bexarotene
“Targretin”
1% Gel
Overall Response Rate is
Complete Response rate is
63%
21%
Because of the irritant effect, it is only used for discrete patch or plaque stage
Not applicable in generalized disease
Apply thin over the lesions twice daily
Irritation is a rule. Withhold for few weeks if erythema
MYCOSIS FUNGOIDES
SHEIKHA
TREATMENT OF MF
RADIATION
THERAPY
MF is an exquisitely radiosensitive neoplasm
Irradiation may be exploited in several ways
Individual plaques or tumors of MF may be treated to total
doses of 15 to 25 Gy in 1 to 3 weeks, with a high likelihood
of 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
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TOTAL SKIN ELECTRON BEAM THERAPY
“Stanford Technique”
OVERALL RESPONSE RATE
COMPLETE RESPONSE RATE
100%
98%
50% OF T1 & 25% OF T2 ARE FREE
OF DISEASE 5 YEARS AFTER A
SINGLE COURSE
Indications:
Very thick plaques
Recent rapid progression
Other local therapy are ineffective
Local N2-Mustard
is indicated for 6
months after
TSEBT
A full cycle takes 2 days
2 Gy is given per cycle
Total dose of around 36 Gy
is given over 10 weeks;
Give a week rest in middle
to give relief from erythema
Complications:
Erythema
Dry desquamation
Alopecia
Nail loss
Sweating problems
MYCOSIS FUNGOIDES
SHEIKHA
MYCOSIS FUNGOIDES
SHEIKHA
TREATMENT OF MF
SYSTEMIC
CHEMOTHERAPY
CHOP
Only for Extracutaneous MF
80% to 100% Complete or Partial Response
Duration of Response is usually < 1 year
COP
CAVE
COMP
MYCOSIS FUNGOIDES
OTHER
TREATMENTS
Extracorporeal
Photopheresis
Recombinant
Fusion Proteins
SHEIKHA
TREATMENT OF MF
Interferon-α
Systemic
Retinoids
IL-2-diphtheria toxin (Ontak; denileukin diftitox)
For IL-2 receptor “CD25+” MF
MYCOSIS FUNGOIDES
SHEIKHA
OUTCOME
STAGE IA (Limited Patch or Plaque, T1) Disease
Excellent Prognosis with conventional Treatment
Life Expectancy = Age Matched Population
Only 9% progress to more advanced stages
Aggressive Therapy has no Survival Advantage
Do not over treat
MYCOSIS FUNGOIDES
SHEIKHA
OUTCOME
STAGE IB/IIA (Generalized Patch or Plaque, T2) Disease
Median Survival of 11 years
25% MR from MF
MYCOSIS FUNGOIDES
SHEIKHA
OUTCOME
STAGE IIB (Tumorous) Disease
Median Survival of 3.2 years
Majority die of MF
MYCOSIS FUNGOIDES
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OUTCOME
STAGE III (Erythrodermic, T4) Disease
Total Skin Electron Beam Therapy is not recommended
Survival is variable
MYCOSIS FUNGOIDES
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OUTCOME
STAGE IV (Extracutaneous) Disease
Poor Prognosis
Median Survival 13 months
MYCOSIS FUNGOIDES
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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
Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome
Girardi M et al. N Engl J Med 2004;350:1978-1988
MYCOSIS FUNGOIDES
SHEIKHA
Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome
MYCOSIS FUNGOIDES
SHEIKHA
Thank You
MYCOSIS FUNGOIDES
SHEIKHA