Thomas Klasifikasi Sezary

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Abstract and IntroductionAbstract

Cutaneous T-cell lymphomas are rare, distinct forms of non-Hodgkin's lymphomas. Of which, mycosis fungoides (MF)and Szary syndrome (SS) are two of the most common forms. Careful, clear classification and staging of theselymphomas allow dermatologists to commence appropriate therapy and allow correct prognostic stratification for thosepatients affected. Of note, patients with more advanced disease will require multi-disciplinary input in determiningspecialist therapy. Literature has been summarized into an outline for classification/staging of MF and SS with the aimto provide clinical dermatologists with a concise review.

Introduction

Primary cutaneous lymphomas (PCL) are rare forms (2%) of non-Hodgkin's lymphomas with an annual incidence of 0.31 per 100,000. [1] These lymphomas include both primary cutaneous T-cell (75%) and B-cell lymphomas definedby presentation at the time of diagnosis without any extracutaneous sites of disease.1 In 2005, the two classificationsystems for cutaneous T-cell lymphoma (CTCL), namely the World Health Organization (WHO) and EuropeanOrganization for Research and Treatment of Cancer (EORTC), were combined, providing distinct subtypes based onclinico-pathologic criteria (). [1,2]

Table 1. WHO-EORTC classification of cutaneous lymphoma with primary cutaneous manifestations 1

Classification

Cutaneous T-cell andNK-cell lymphomas

Mycosis fungoides

MF variants and subtypes

Folliculotropic MF

Pagetoid reticulosis

Granulomatous slack skin

Szary syndrome

Adult T-cell leukemia/lymphoma

Primary cutaneous CD30+lymphoproliferative disorders

Primary cutaneous anaplastic large celllymphoma

Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell

lymphoma

Extranodal NK/T-cell lymphoma,

A Practical Approach to Accurate Classification and Staging of Mycosis Fungoides and Szary SyndromeBjorn Rhys Thomas, MBBS, Sean Whittaker, MB, MD, FRCP

Skin Therapy Letter. 2012;17(10)
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nasal type

Primary cutaneous peripheral T-celllymphoma, unspecified

Primary cutaneous aggressive epidermotropicCD8+ T-cell lymphoma (provisional)

Cutaneous gamma/delta T-cell lymphoma(provisional)

Primary cutaneous CD4+ small/medium-sizedpleomorphic T-cell lymphoma (provisional)

Cutaneous B-celllymphomas

Primary cutaneous marginal zone B-cell lymphoma

Primary cutaneous follicle center lymphoma

Primary cutaneous diffuse large B-

cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lymphoma, other

Intravascular large B-cell lymphoma

Precursor hematologicneoplasm

CD4+/CD56+ hematodermicneoplasm (blastic NK-celllymphoma)

Mycosis fungoides (MF) represents the most common variant of CTCL [3] and is characterized by a monoclonalproliferation of epidermotropic CD4+/CD45RO+ T-cells often with aberrant expression of mature T-cell antigens. [1,4]

MF (Alibert-Bazin type) is characterized by the presence of polymorphic patches, plaques, and tumors. [1] Szarysyndrome (SS) is a rare CTCL variant closely related to MF and has classically been described as a triad of erythroderma, generalized lymphadenopathy and Szary cells (atypical neoplastic T lymphocytes withhyperconvoluted cerebriform nuclei) in the skin, blood, and lymph nodes. [1,5,6] The WHO-EORTC system currentlydistinguishes SS as a separate entity from MF, but rare cases of SS preceded by typical MF have been described. [3,7]

In this article, we will focus primarily on the evaluation and classification of these conditions and summarize theavailable therapies.

Evaluation

A confident diagnosis of MF can only be made from a combination of clinical and pathologic findings. Characteristicpathologic features include cytologically atypical lymphocytes with cerebriform nuclei (described above) either colonizing the basal layer of the epidermis (epidermotropism) or forming clusters of cells in the epidermis (Pautrier microabscesses) with or without a band of cytologically atypical cells in the upper dermis. [1,8,9] An algorithm for thediagnosis of early-stage MF has been suggested by the International Society of Cutaneous Lymphoma (ISCL), whichincludes clinico-pathological correlation and immunophenotypic and clonal T-cell receptor gene rearrangementstudies, providing minimum criteria for diagnosis (). [2,8] For SS, ISCL recommends the presence of erythroderma andthe demonstration of the same T-cell clone (using polymerase chain reaction [PCR] or Southern blot of the T-cellreceptor [TCR] gene) in skin and blood plus one of the following: Szary cell count >1000 cells/mm 3; expanded CD4+population with CD4/CD8 ratio >10; or loss of T-cell antigens (CD2, CD3, CD4, CD5 and CD7). [1] It must beappreciated that the diagnosis of early MF can be difficult and repeated biopsies may be required. [2,8] Careful clinico-pathological evaluation with a dermatologist and experienced pathologist in PCLs is recommended ().


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Table 2. An algorithm for diagnosing early MF* (ISCL) 2,3

Criteria Scoring*

Essential Additional Other Major (2points)

Minor (1Point)

Clinical

Persistentand/or progressivepatches/thinplaques

1. Non-sunexposed location

2. Size/shapevariation

3. Poikiloderma

Any 2additionalcriteria

Any 1additionalcriteria

HistopathologicSuperficiallymphoid

infiltrate

1. Epidermotropism

2. Lymphoid atypia

Any 2additional

criteria

Any 1additional

criteria

Molecular biological

Clonal TCR generearrangement

N/A Present

Immunopathologic

1. CD2+, CD3+ and/or CD5+ >50% of T cells

2. >10% CD7+ T cells

3. Epidermal/dermaldiscordance of CD2+,CD3+, CD5+ or CD7-(T cell antigen lossconfined to epidermis)

N/A

Any 1

additionalcriteria

*A total of 4 points is required to make a diagnosis of MF

Table 3. Evaluation/staging of patients with MF/SS 2,3

Evaluation/StagingPhysicalexam

Skin lesions

If patch/plaques or erythroderma: determine percentage of bodysurface area and note any ulceration

If tumors: note the total number, largest lesion, and regionsaffected

Lymph nodes Note: if >1.5 cm or firm, irregular, clustered, or fixed

Organomegaly Present/not present


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Skinbiopsy

SiteMost indurated area and compare plaques to tumors

The site should be free from topical steroid for at least 2 weeks

Tests

Immunophenotyping for CD2/3/4/5/7/8 and B-cell markers such asCD20, CD79a, as well as other markers such as CD56 and Ki67may be indicated

TCR gene analysis for clonal TCR gene rearrangements

Bloodstests

CBC, liver function tests, LDH and chemistries

TCR gene analysis - to compare with tissue biopsy

Analyze any abnormal lymphocytes - Szary cell count and/or flowcytometry (CD4+/CD7- or CD4+/CD26-)

Radiology

Chest X-ray in T 1-2 N0B0 with limited skin involvement and no organ

specific complaints

CT scan of chest, abdomen, and pelvis for all other groups. Role of FDG-PET scan has yet to be defined

Lymphnodebiopsy

Which node? Excisionbiopsy or core biopsypreferred to FNA

If nodes >1.5 cm or firm, irregular, clustered, or fixed

Choose largest node draining an involved area or the node with thehighest standardized uptake value from FDG-PET scan

Tests Light microscopy/immunophenotypic studies/TCR gene analysis

CBC = complete blood count FDG-PET = fluorodeoxyglucose-positron emission tomography; FNA = fine-needle

aspiration; TCR = T-cell receptor

Classification/Staging

The management of MF/SS is a stage-based approach derived from the TNM (tumor-node-metastasis) Classificationof Malignant Tumours (). Patients with Stage IA, IB or IIA have an early stage disease compared to IIB (tumor), III(erythroderma), and IV (pathologically involved nodes - IVA; visceral involvement - IVB) have advanced-stage disease().[2] Of note, there are two main classifications for lymph node involvement. The Dutch system defines atypical cellsas cerebriform cells with a diameter >7.5 m - increasing grade is associated with increased involvement of thesecells. [10] The second system, the National Cancer Institute and Veteran's Administration Hospital (NCI-VA)

classification focuses primarily on the number of cells within the paracortex of the lymph node and their subsequenteffect on the structure of the node. [11]


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Table 4. Classification of MF/SS (ISCL/EORTC revision) 2,3,10,11

TNMClassification

Features

Skin T 1 Patches*, papules and/or plaques 10% of body surface (T2a: Patch - T2b: Plaque +/- patch)

T3 One or more tumors (>1 cm diameter)

T4 Confluent erythema >80% of body surface

Node N 0 No abnormal peripheral lymph nodes (LN) - no biopsy required

N1 Abnormal LN - Dutch grade 1 - dermatopathic lymphadenopathy (DL) - NCI-VA + LN0-2 (N1a : Clone -

N1b : Clone +) - occasional to many lymphocytes

N2 Abnormal LN - Dutch grade 2 - DL: early atypical lymphocyte involvement - NCI-VA LN 3 (N2a : Clone

- N2b

: Clone +) - aggregates of atypical lymphocytes

N3

Abnormal LN - Dutch grade 3 - many atypical lymphocytes with partial effacement of LN - Dutchgrade 4 - complete effacement of LN - NCI-VA LN 4 (N3a : Clone - N 3b : Clone +) - partial/complete

effacement of LN

Nx Abnormal lymph nodes - no confirmatory histology

Visceral M 0 No visceral organs involved

M1 Viscera involved (with pathological confirmation - imaging for spleen/liver)

Blood B 0 >5% of peripheral blood lymphocytes are Szary cells (B 0a : Clone - B 0b : Clone +)B1 >5% of peripheral blood lymphocytes are Szary cells (B 1a : Clone - B 1b : Clone +)

B2 High tumour burden: ! 1000/L Szary cells with Clone +

* Patches are without elevation or induration; + National Cancer Institute and Veteran's Administration Hospitalclassification

Table 5. Staging of MF/SS (ISCL/EORTC revision) 2,3

Limited-stage Disease

IA T1, N0, M0, B0-1

IB T2, N0, M0, B0-1

IIA T1-2, N1-2, M0, B0-1

Advanced-stage Disease

IIB T3, N0-2, M0, B0-1

IIIA T4, N0-2, M0, B0

IIIB T4, N0-2, M0, B1

IVA1 T1-4, N0-2, M0, B2


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IVA2 T1-4, N3, M0, B0-2

IVB T1-4, N0-3, M1, B0-2

T1-4: tumor stage; N0-3: nodal stage; M0-1: visceral organs; B1-2: peripheral blood

Prognosis

The prognosis of MF/SS is primarily based on stage, particularly the extent/type of lesions and presence of extracutaneous disease, [1,2] emphasising the importance of thorough patient workup. Of note, MF/SS are thought asincurable diseases but the majority of patients with MF have an indolent disease course with 6585% of patients beingstage IA or IB at diagnosis. [2,1214]

Patients with stage IA disease have a median survival of more than 12 years and no decrease in survival whencompared to an age-, sex- and race-match control population. [1,2,1517] It is now appreciated that for patients withstage IB, the presence of plaques (T2b) is associated with a worse prognosis and increased risk of diseaseprogression when compared to those with only patches (T2a). [12]

In contrast, patients with more advanced stage disease (stages IIB, III, IVA) have a median survival of 5 years andstage IVB patients have a median survival of 2.5 years. [2,12,13,15,17] More specifically, patients with dermatopathicnodes (N1) also have a poorer survival when compared to those with no palpable nodes (N0). The presence of abnormal nodes with no histological confirmation (Nx) is also associated with mortality/poor outcome. [14] A recentstudy also showed that patients with stage B0b (


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and radiotherapy. Long-term durable remissions are rare. Total skin electron beam (TSEB) therapy andimmunobiologics are key options for patients with disease that is resistant to skin-directed treatments. Patients inadvanced disease stages often receive chemotherapy but responses are rarely sustained. Several novel agents suchas fusion toxins (denileukin diftitox), bexarotene, and histone deacetylase (HDAC) inhibitors have received US FDAapproval during the last few years and offer promising alternatives to chemotherapy. Similarly, data on antibodies suchas alemtuzumab suggests significant and occasionally durable responses. summarizes many of the availabletherapies.

Table 7. Summary of therapies available for MF/SS 2,19

Therapy

MF SS/Erythrodermic

Comments*Limitedstage

Advancedstage

MF

Expectant therapy** +++ Stage IA with steroid if needed

Topical corticosteroids ++++ ++ +++Symptom control/complete responses mayoccur

Psoralen + ultraviolet A(PUVA)

++++ + +++ Rate of durable remission is low

UVB (TLO1)phototherapy

+++ + ++ More effective for patches

Topical chemotherapy ++ Limited availability currently

Imiquimod + Small/limited lesions

Photodynamic therapy + Limited evidence and causes severe pain

Retinoids + + + Usually second-line

Bexarotene ++ +++ +++Can be used with PUVA or interferon-alphaFDA/EMA approved

Interferon-alpha ++ ++++ ++++ EMA approved

HDACi (vorinostat;romidepsin)

+ ++++ ++++ FDA approved

Oral methotrexate + ++ +++ Low dose weekly for stage III

Radiotherapy ++++ ++Highly effective for localized large

plaques/tumour/nodules

Total skin electronbeam (TSEB)

++ +++ + For widespread disease

Systemic chemotherapy +++ ++ High response rates but short duration

Extracorporealphotopheresis (ECP)

+ + ++++Evidence suggests that best for patients withperipheral blood involvement

Autologoustransplantation

+ + Not associated with durable remissions

Allogenic Reduced intensity regimens offer promising


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transplantation ++ ++ option for selected patients with advanceddisease

Denileukin diftitox +++ +++ Limited availability at present

Alemtuzumab + +++ OasdfRDP

Proteasome inhibitors Under investigation

Immunomodulatoryagents (lenalidomide)

Under investigation

+ = frequency of use; * Refer to National Cancer Center Network and EORTC consensus recommendations for further guidelines and information regarding therapy for MF/SS; ** Active surveillance - reviewing at regular intervals andreserving treatment for disease-related symptoms; EMA = European Medicines Agency

Conclusion

Appropriate therapy for advanced stages of MF/SS can only be initiated based on a multi-disciplinary approach(including dermatologists, pathologists, and oncologists) to classification and staging. Accurate staging and work-upwill allow appropriate therapy and prognostic details to be delivered to each individual patient.

References

1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May15;105(10):376885.

2. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sezary syndrome. Blood. 2009 Nov12;114(20):433753.

3. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides andSezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneouslymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood.2007 Sep 15;110(6):171322.

4. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological andmolecular aspects. J Cutan Pathol. 2005 Nov;32(10):64774.

5. Wieselthier JS, Koh HK. Sezary syndrome: diagnosis, prognosis, and critical review of treatment options. J Am Acad Dermatol. 1990 Mar;22(3):381401.

6. Akilov OE, Geskin L. Therapeutic advances in cutaneous T-cell lymphoma. Skin Therapy Lett. 2011Feb;16(2):15.

7. Diwan AH, Prieto VG, Herling M, et al. Primary Sezary syndrome commonly shows low-grade cytologic atypiaand an absence of epidermotropism. Am J Clin Pathol. 2005 Apr;123(4):5105.

8. Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005Dec;53(6):105363.

9. Guitart J, Kennedy J, Ronan S, et al. Histologic criteria for the diagnosis of mycosis fungoides: proposal for a

grading system to standardize pathology reporting. J Cutan Pathol. 2001 Apr;28(4):17483.

10. Sausville EA, Worsham GF, Matthews MJ, et al. Histologic assessment of lymph nodes in mycosis


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fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a newclassification system. Hum Pathol. 1985 Nov;16(11):1098109.

11. Scheffer E, Meijer CJ, Van Vloten WA. Dermatopathic lymphadenopathy and lymph node involvement inmycosis fungoides. Cancer. 1980 Jan 1;45(1): 13748.

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13. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides andSezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003Jul;139(7):85766.

14. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosisfungoides/Sezary syndrome: validation of the revised International Society for CutaneousLymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol.2010 Nov 1; 28(31):47309.

15. Zackheim HS, Amin S, Kashani-Sabet M, et al. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol. 1999 Mar;40(3):41825.

16. van Doorn R, Van Haselen CW, van Voorst Vader PC, et al. Mycosis fungoides: disease evolution andprognosis of 309 Dutch patients. Arch Dermatol. 2000 Apr;136(4):50410.

17. Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood. 1996 Oct1;88(7):2385409.

18. Heald P, Latkowski J, Wilson L, et al. Successful therapy of cutaneous T-cell lymphoma. Expert Rev of Dermatol. 2008 Feb;3(1):99110(12).

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