MYCOSIS FUNGOIDES

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


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


Professor Lennert, Keil Classification

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

*


http://content.nejm.org/content/vol350/issue19/images/large/11t1.jpeg


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


Patch Plaque TumorStage

SézarySyndrome

MF patches are usually distributed in sun-shielded areas such as those covered by a bathing suit or intertriginous regions.

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C1541patch1.jpg&template=izoom2

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C1541plaque1.jpg&template=izoom2

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C1541sezary1.jpg&template=izoom2

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C1541cell1.jpg&template=izoom2

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C1541tumor1.jpg&template=izoom2

Various Cutaneous Manifestations of Mycosis Fungoides


The cardinal features of MF is infiltration of epidermis and then dermis by Atypical Cerebriform Lymphoid Cells

EPIDERMOTROPIC

http://content.nejm.org/content/vol329/issue27/images/large/05f1.jpeg

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C1541cell1.jpg&template=izoom2

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 =

Pautrier Abscesses


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


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


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


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


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.


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


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


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


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


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



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


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


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


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


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


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


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


OTHERTREATMENTS

TREATMENT OF MF

ExtracorporealPhotopheresis

Interferon-αSystemicRetinoids

RecombinantFusion Proteins

IL-2-diphtheria toxin (Ontak; denileukin diftitox)For IL-2 receptor “CD25+” MF


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


OUTCOME

STAGE IB/IIA (Generalized Patch or Plaque, T2) Disease

Median Survival of 11 years25% MR from MF


OUTCOME

STAGE IIB (Tumorous) Disease

Median Survival of 3.2 yearsMajority die of MF


OUTCOME

STAGE III (Erythrodermic, T4) Disease

Total Skin Electron Beam Therapy is not recommended

Survival is variable


OUTCOME

STAGE IV (Extracutaneous) Disease

Poor PrognosisMedian Survival 13 months


REVISON


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.


Panel B shows pagetoid reticulosis, a variant of mycosis fungoides that typically consists of a single patch or plaque located in an acral area.


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.


Panel D shows follicular mycosis fungoides, in which lesions characterized by alopecia develop. In a similar variant, there is mucin deposition in the follicles.


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.


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.


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.


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


Let me now examine you


THANK YOU

Girardi M et al. N Engl J Med 2004;350:1978-1988

Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome


Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome

Blood of a Cutaneous T-cell Lymphoma Patient

showing Sézary cells

Pautrier microabscess


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.


http://content.nejm.org/content/vol350/issue19/images/large/11t4.jpeg


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


TREATMENT OF MF

SYMPTOMATIC:

Pruritus & xerosis could be severeR/ Aggressive emolliation, topical steroid & oral antipruritics Dermatologists

MF TREATMENT:


PHOTO-THERAPY

TOPICALRETINOIDS

RADIATIONTHERAPY

SYSTEMICCHEMO-THERAPY

Extracorporeal PhotopheresisInterferon –αRetinoidsRecombinant Fusion ProteinsCombined Modality Therapy

Mycosis fungoides

Mycosis fungoides lymph node involvement


Plaque Stage: A broad band-like cellular infiltrate in the upper dermis


Patch Plaque

TumorStage

SézarySyndrome

MYCOSIS FUNGOIDES

Documents

Transcript of MYCOSIS FUNGOIDES