MYCOSIS FUNGOIDES SHEIKHA

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MYCOSIS FUNGOIDES

SHEIKHA
MYCOSIS FUNGOIDES
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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
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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
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SEZARY SYNDROME
MF/SZ
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Professor Lennert, Keil Classification
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W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS
B
T NK
NHL
Precursor T-cell neoplasms
Precursor B-cell neoplasms

Mature (Peripheral) B-cell neoplasms
Mature (Peripheral) T-cell neoplasms
Nodular Lymphocyte-Predominant Hodgkin
Lymphoma Classical Hodgkin Lymphoma
HD
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W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS
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 Hepatosple
nic ?d 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 Angioimmu
noblastic T-cell Lymphoma Anaplastic Large-cell
Lymphoma/T/null, systemic type
NHL
T NK
Mature (Peripheral) T-cell neoplasms

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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
TUMOR STAGE
PATCH STAGE
PLAQUE STAGE
ERYTHRODERMA SEZARY
Cerebriform Sezary Cells
Epidermo- tropism
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Patch
Plaque
Tumor Stage
MF patches are usually distributed in
sun-shielded areas such as those covered by a
bathing suit or intertriginous regions.
Sézary Syndrome
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Various Cutaneous Manifestations of Mycosis
Fungoides
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EPIDERMOTROPIC
The cardinal features of MF is infiltration of
epidermis and then dermis by Atypical
Cerebriform Lymphoid Cells
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Mycosis Fungoides A Cancer of Skin-Homing T Cells
Girardi M et al. N Engl J Med 20043501978-1988
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Multiple discrete confluent plaques of
cutaneous T-cell lymphoma MF
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Multiple plaques of cutaneous T-cell lymphoma
with tumor formation MF
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• PATCH STAGE
• Mild epidermal hyperplasia with
• perivascular or band-like infiltrate
• of small- to medium-sized atypical
• lymphocytes with cerebriform nuclear
• convolution.
• EPIDERMOTROPISM
• Cerebriform lymphocytes exhibit
• epidermotropism and are arranged
• along the dermal-epidermal junction
• in a single-file pattern or scattered
• in the epidermis.
• Pautriers microabscesses are small
• intra-epidermal collections of cerebriform
• lymphocytes are pathognomonic for
• MF. They might not be present in early

MF PATCHES
Eczematoid
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2. PLAQUE STAGE The density of the neoplastic
cells within dermis increases Exaggerated
epidermotropism
Psoriasiform
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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
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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 demblee ?????
Tumors could get infected ? sepsis ? death
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ERYTHRODERMA Pathology similar to Patch
stage but infiltrate is more sparse Generalized
erythroderma with Sézary cells with
cerebriform nuclei in blood of gt1,000/uL ?
Sézary Syndrome ?CD4 to CD8 ratio gt101 T-cell
Receptor gene rearrangement
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Intensely symptomatic from pruritus
scaling Usually have lymphadenitis
Sézary Syndrome
Generalized erythroderma
Lympha- denopathy
Sézary cells
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Pautrier Abscesses
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LYMPH NODE INVOLVEMENT IN MF or
SZS DERMATOPATHIC LYMPHADENITIS DL
CATEGORY III LN4 CATEGORY II LN3 CATEGORY I LN0-LN2
Partial or complete effacement of LN architecture by cytologically atypical lymphocyte Clusters of 10 or more atypical LC confined to the paracortex DL LN0 DL/ No atypical LC LN1 Scattered atypical cerebriform LC (not in clusters) DL LN2 Small clusters lt 6 cells DL
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IMMUNOPHENOTYPE in MF/SZS
CD2
CD7-
CD30-
CD3
CD4
Molecular Diagnosis PCR of T-cell Receptor
? rearrangement, especially in early patch stages
CD5
CD25 -/
Cell of Origin CD4 T lymphocyte with
skin homing epidermotropic properties
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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
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CLINICAL PRESENTATION OF MF
30 Limited patch or plaque stage lt10 BSA
T1
35-40 Generalized patch or plaque stage gt10
BSA T2
15-20 Tumorous stage lt10 BSA T3
PRURITUS Commonest symptom of MF
15 Erythro- derma T4
Only 15 of MF patients show extracutaneous
disease. Lymph nodes Visceral disease, etc
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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.
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Various Cutaneous Manifestations of Mycosis
Fungoides
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STAGING OF MF
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(SKIN) T
Limited patch/plaque (lt10 total skin surface) T1
Generalized patch/plaque (gt10 total skin surface) T2
Tumors T3
Generalized Erythroderma T4
(VISCERA) M
No Visceral involvement M0
Visceral involvement M1
Tumor- Node- Metastasis- Blood Classification For
MF
(BLOOD) B
No Sézary cells (lt5 of LC) B0
Circulating Sézary cells (gt5 of LC) B1
(LYMPH NODES) N
LN Clinically uninvolved N0
Enlarged histologically uninvolved (reactive dermatopathic) N1
LN Clinically uninvolved histologically involved N2
LN enlarged involved N3
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CLINICAL STAGING SYSTEM FOR MF
M N T Clinical stages
M0 N0 T1 IA
M0 NO T2 IB
M0 N1 T1-2 IIA
M0 N0-1 T3 tumor IIB
M0 N0 T4 IIIA Erythroderma
M0 N1 T4 IIIB Erythroderma
M0 N2-3 histology T1-4 IVA
M1 N0-3 T1-4 IVB
B CLASSIFICATION (SEZARY CELLS) DOES NOT ALTER
CLINICAL STAGE
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(SKIN) T
Limited patch/plaque (lt10 total skin surface) T1
Generalized patch/plaque (gt10 total skin surface) T2
Tumors T3
Generalized Erythroderma T4
(VISCERA) M
No Visceral involvement M0
Visceral involvement M1
(BLOOD) B
No Sezary cells (lt5 of LC) B0
Circulating cells (gt5 of LC) B1
M N T Clinical stages
M0 N0 T1 IA
M0 NO T2 IB
M0 N1 T1-2 IIA
M0 N0-1 T3 IIB
M0 N0 T4 IIIA
M0 N1 T4 IIIB
M0 N2-3 T1-4 IVA
M1 N0-3 T1-4 IVB
(LYMPH NODES) N
LN Clinically uninvolved N0
Enlarged histologically uninvolved (reactive dermatopathic) N1
LN Clinically uninvolved histologically involved N2
LN enlarged involved N3
Tumor-Node-Metastasis-Blood Clinical Staging
Classification
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TOPICAL CHEMO- THERAPY
TREATMENT OF MF
Effective
TOPICAL NITROGEN MUSTARD MECHLORETHAMINE"
Mechanism ??
AQUEOUS SOLUTION
OINTMENT
10 to 20 mg Per 100 cc

Choice of aqueous or ointment depends on
convenience, preference cost Hypersensitivity
is 30 with Aqueous solution lt 5 with ointment
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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 gt 10 years
Local Radiation to Refractory local lesions
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TOPICAL CHEMO- 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
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PHOTO- THERAPY
TREATMENT OF MF
Ultraviolet Light (UV) ? UVA or UVB wavelength
Psoralen PUVA Psoralen 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 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 ( gt6 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
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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
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TOPICAL RETINOIDS
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 stage Not applicable
in generalized disease Apply thin over the
lesions twice daily Irritation is a rule.
Withhold for few weeks if erythema
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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
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TOTAL SKIN ELECTRON BEAM THERAPY Stanford
Technique
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
OVERALL RESPONSE RATE 100 COMPLETE RESPONSE
RATE 98 50 OF T1 25 OF T2 ARE FREE OF
DISEASE 5 YEARS AFTER A SINGLE COURSE
Local N2-Mustard is indicated for 6 months after
TSEBT
Complications Erythema Dry desquamation Alopeci
a Nail loss Sweating problems
Indications Very thick plaques Recent rapid
progression Other local therapy are ineffective
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TREATMENT OF MF
SYSTEMIC CHEMO- THERAPY
Only for Extracutaneous MF 80 to 100 Complete
or Partial Response Duration of Response is
usually lt 1 year
CHOP
COP
CAVE
COMP
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TREATMENT OF MF
OTHER TREATMENTS
Extracorporeal Photopheresis
Interferon-a
Systemic Retinoids
Recombinant Fusion Proteins
IL-2-diphtheria toxin (Ontak denileukin
diftitox) For IL-2 receptor CD25 MF
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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
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OUTCOME
STAGE IB/IIA (Generalized Patch or Plaque, T2)
Disease Median Survival of 11 years 25 MR from
MF
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OUTCOME
STAGE IIB (Tumorous) Disease Median Survival of
3.2 years Majority die of MF
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OUTCOME
STAGE III (Erythrodermic, T4) Disease Total Skin
Electron Beam Therapy is not recommended Survival
is variable
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OUTCOME
STAGE IV (Extracutaneous) Disease Poor
Prognosis Median Survival 13 months
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REVISON
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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 "nonmycosis fungoides cutaneous
T-cell lymphoma
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Various Cutaneous Manifestations of Mycosis
Fungoides
Let me now examine you
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THANK YOU
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Therapeutic Options in the Management of Mycosis
Fungoides and the Sezary Syndrome
Girardi M et al. N Engl J Med 20043501978-1988
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Therapeutic Options in the Management of Mycosis
Fungoides and the Sezary Syndrome
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ATCLL
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Blood of a Cutaneous T-cell Lymphoma Patient
showing Sézary cells
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Pautrier microabscess
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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-functionass
ociated 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.
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WHAT TO REMEMBER ABOUT MF
It is an indolent troublesome disease Flat
patches, thin plaques, deep tumors
Erythroderma Cerebriform cells Epidermotropism The
patient has to live with it in the majority of
cases
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TREATMENT OF MF
SYMPTOMATIC Pruritus xerosis could be
severe R/ Aggressive emolliation, topical
steroid oral antipruritics
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Dermatologists
MF TREATMENT
TOPICAL CHEMO- THERAPY
PHOTO- THERAPY
TOPICAL RETINOIDS
SYSTEMIC CHEMO- THERAPY
RADIATION THERAPY
Extracorporeal Photopheresis Interferon
a Retinoids Recombinant Fusion Proteins Combined
Modality Therapy
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Mycosis fungoides
Mycosis fungoides lymph node involvement
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Plaque Stage A broad band-like cellular
infiltrate in the upper dermis
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Tumor Stage
Patch
Plaque
Sézary Syndrome