Introduction to Cutaneous Lymphomas

Rein Willemze Professor of Dermatology Dept. of Dermatology; Leiden University Medical Center Leiden, The Netherlands ERN-EuroBloodNet Cutaneous Lymphomas May 18, 2020 NO CONFLICT OF INTEREST TO DISCLOSE Cutaneous Lymphoma Webinars

• Introduction to Cutaneous Lymphoma: Rein Willemze

• Mycosis Fungoides: Maarten Vermeer

• Sézary Syndrome: Martine Bagot & Pietro Quaglino

• CD30+lymphoproliferations: Werner Kempf

• Aggressive T-cell lymphomas: Pietro Quaglino & Evangelia Papadavid

• Indolent CBCL (PCFCL and PCMZL): Pablo Ortiz & Emmanuella Guenova

• Aggressive CBCL (PCDLBCL-LT): Marie Beylot Barry & Anne Pham-Ledard

• New therapeutic developments I: Julia Scarisbrick

• New therapeutic developments II: Rudolf Stadler To be discussed

➢ Basic concepts in cutaneous lymphoma diagnosis.

➢ Why are cutaneous lymphomas special (different from nodal NHL) ?

➢ History of cutaneous lymphoma classification • dictates the type of treatment • provides information on clinical course and prognosis. • incorrect classification → incorrect treatment History of cutaneous lymphoma classification

1806 Mycosis fungoides (MF) 1862 Three tumor stages MF (Bazin) 1938 Sézary syndrome 1939 Pagetoid reticulosis (localized) 1968 Lymphomatoid papulosis

1975 Cutaneous T-cell Lymphoma (CTCL) proposed as an encompassing term for above conditions.

Mr. Lucas; 1st MF patient described by Alibert (1806)

Lutzner M. et al; Ann Intern Med 1975;83:534-542 Edelson R. J Am Acad Dermatol 1980;2:89-106 History of cutaneous lymphoma classification: 1990

Cutaneous lymphoma (non-MF/SS)

- ca. 40% of cutaneous lymphomas - classified by pathologist with schemes used for nodal lymphomas and based on morphology (histologic classification: Kiel classification; Working Formulation). - No distinction between primary and secondary cutaneous lymphomas. - Primary cutaneous lymphomas (non-MF/SS) did not exist and were treated as systemic lymphomas with secondary skin involvement.

6 History of cutaneous lymphoma classification: 1990

Cutaneous lymphoma (non-MF/SS) (Updated) Kiel classification Low grade (B-cell) Low grade (T-cell) - ca. 40% of cutaneous lymphomas • Small lymphocytic (B-CLL) • Small lymphocytic (T-CLL) - classified by pathologist with schemes used • Lymphoplasmacytic/-cytoid • Small cerebriform (MF/SS) for nodal lymphomas and based on • Centroblastic/centrocytic • Lennert’s lymphoma (follicular and/or diffuse) • AILD morphology (histologic classification: • Small pleomorphic Kiel classification; Working Formulation). - No distinction between primary and High grade (B-cell) High grade (T-cell) secondary cutaneous lymphomas. • Centroblastic • Pleomorphic medium/large • Immunoblastic • Immunoblastic - Primary cutaneous lymphomas (non-MF/SS) • Large cell anaplastic • Large cell anaplastic did not exist and were treated as systemic • Lymphoblastic • Lymphoblastic lymphomas with secondary skin involvement. Rare types Rare types

7 New concepts in cutaneous lymphoma classification

▪ Primary ≠ secondary cutaneous lymphomas.

▪ Diagnosis cannot be based on histology alone (histologic diagnosis ≠ final diagnosis).

▪ Clinical presentation (localization !!) major diagnostic adjunct clinicopathologic correlation essential. Centroblastic lymphoma

(Updated) Kiel classification

Low grade (B-cell) • Small lymphocytic (B-CLL) • Lymphoplasmacytic/-cytoid • Centroblastic/centrocytic (follicular and/or diffuse)

High grade (B-cell) • Centroblastic • Immunoblastic • Large cell anaplastic • Lymphoblastic

Rare types Centroblastic lymphoma

Examination: multiple tumors on the face

Histology: CBCL, centroblastic = diagnosis

Staging: localisations in skin and lymph nodes

Therapy: multi-agent chemotherapy (consistent with centroblastic lymphoma) → CR

Follow-up: died of lymphoma 32 months after diagnosis. Centroblastic lymphoma

(Updated) Kiel classification

Low grade (B-cell) • Small lymphocytic (B-CLL) • Lymphoplasmacytic/-cytoid • Centroblastic/centrocytic (follicular and/or diffuse)

High grade (B-cell) • Centroblastic • Immunoblastic • Large cell anaplastic • Lymphoblastic

Rare types Centroblastic lymphoma

Examination: localized tumors on the trunk

Histology: CBCL, centroblastic = diagnosis

Staging: no localisations in lymph nodes and BM

Therapy: multi-agent chemotherapy (consistent with centroblastic lymphoma) → CR

Follow-up: sustained CR (168 months). Centroblastic lymphoma presenting with only skin lesions Histologic growth pattern of PCFCL

diffuse large cell (CB): >70% Follicular: <5% Follicular & diffuse: 25% No difference in prognosis between cases with follicular, follicular and diffuse and diffuse growth pattern Primary cutaneous ≠ nodal centroblastic lymphoma

• Solitary or localized lesions on trunk or face/scalp (85%) • Therapy: radiotherapy • Skin relapses: ca. 30% (NO disease progression) • Extracutaneous dissemination uncommon (<10%) before radiotherapy • Excellent prognosis (5-yr survival > 90%). • Distinct clinicopathologic entity (derived from follicle center (germinal center) B-cells: primary cutaneous follicle center cell lymphoma

after radiotherapy

Willemze R. et al, Am J Pathol 1987;126:325-333; Berti E. et al; J Am Acad Dermatol 1988;19:259-272 Primary vs secondary cutaneous lymphomas

Primary Cutaneous Lymphoma (PCL): • malignant lymphoma presenting in the skin • No evidence of extracutaneous disease at time diagnosis as assessed by appropriate staging procedures.

Secondary CL (skin localizations of NHL) • NHL with both cutaneous and extracutaneous localizations at diagnosis • Skin localizations in a patient with a history of a systemic NHL 17 Primary CBCL defined between 1986 and 1995

Low grade (B-cell) • Small lymphocytic (B-CLL) Primary cutaneous • Lymphoplasmacytic/-cytoid immunocytoma (PCMZL) (5-yr-survival: 99%) immunocytoma • Centroblastic/centrocytic (follicular and/or diffuse) Primary cutaneous follicle High grade (B-cell) center cell lymphoma (5-yr-survival: >95%) • Centroblastic • Immunoblastic • Large cell anaplastic • Lymphoblastic Primary cutaneous diffuse large B-cell lymphoma, leg (5-yr-survival: 50%) Rare types

Willemze R et al: BLOOD 1997;90: 354-371 CTCL other than MF/SS in 1988

Low grade (T-cell) = small cell • Small lymphocytic (T-CLL) • Small cerebriform (MF/SS) Primary cutaneous CD30-negative • Lennert’s lymphoma large T-cell lymphoma • AILD • Small pleomorphic (5-yr-survival: <20%)

High grade (T-cell) = large cell • Pleomorphic medium/large • Immunoblastic Primary cutaneous CD30-positive • Large cell anaplastic large T-cell lymphoma • Lymphoblastic (5-yr-survival: >90%) Rare types

Beljaards RC. Et al; Am J Pathol. 1989;135:1169-78. 18 PCL vs nodal NHL -/+ secondary cutaneous involvement

• Distinctive clinical features (disease entities)

• Other clinical behaviour and prognosis → different type of treatment.

• Other biologic features (e.g. genetic pathways; translocations; adhesion molecules) → different pathogenesis.

• PCL should be included as separate entities in malignant lymphoma classifications (to prevent unnecessarily aggressive therapies). PCL vs nodal NHL -/+ secondary cutaneous involvement

Primary cutaneous lymphomas are visible and accessible: • Different types of CTCL and CBCL have a characteristic clinical presentation that may be helpful in diagnosis and classification. • Different types of cutaneous lymphoma can show an identical histology → classification on the basis of histology alone impossible. • Histologic diagnosis = differential diagnosis ≠ final diagnosis → clinicopathologic correlation essential • CTCL is not a diagnosis ! Centroblastic lymphoma presenting with only skin lesions

Localized skin lesions on trunk (back) or scalp (>80%) Primary cutaneous marginal zone lymphoma

Preferential localization on arms and upper trunk (65%) Primary cutaneous DLBCL, leg type

Preferential localization on leg(s) in elderly patients (>80%) Early stage mycosis fungoides Folliculotropic mycosis fungoides

Characteristic infiltration of eyebrow region with loss of hair Primary cutaneous acral CD8+ T-cell lymphoma

Petrella T. et al. Am J Surg Pathol. 2007;31:1887-9 PCL vs nodal NHL -/+ secondary cutaneous involvement

Epidermotropic T-cells

CD3

Characteristic presentation of MF for Characteristic presentation of MF for dermatologists pathologists Epidermotropic atypical infiltrate: MF?

MF ? MF ? MF ? MF ? Epidermotropic atypical infiltrate: MF?

MF Aggressive Lymphomatoid Lichen sclerosus CD8+ CTCL papulosis Epidermotropic CD8+ CTCL (superficial infiltrates)

mycosis fungoides pagetoid reticulosis LyP, type D aggressive CD8+ CTCL DD. Diffuse CD30-positive skin infiltrate

Examination: nodules and ulcerating tumors on left upper leg for 2 months.

Histology: (C-)ALCL = diagnosis ?

Staging: no extracutaneous disease

Therapy: ?

CD3 CD30 DD. Diffuse CD30-positive skin infiltrate

Skin infiltrates with clusters of CD30+ cells: • Cutaneous anaplastic large cell lymphoma (C-ALCL) • Lymphomatoid papulosis (type C) • Mycosis fungoides with large cell transformation (CD30+) • Skin localizations systemic ALCL (ALK+ or ALK-) • Skin localizations of Hodgkin lymphoma. • MTX-associated B-cell lymphoproliferative disorder • Benign skin disease. DD. Diffuse CD30-positive skin infiltrate

Examination: nodules and ulcerating tumors on left upper leg for 2 months.

Histology: (C-)ALCL = diagnosis ? ? Diffuse CD30+ dermal infiltrate; DD: (C-)ALCL; transformed MF

Staging: no extracutaneous disease

Therapy: ?

CD3 CD30 DD. DiffuseMan, 74 yrs.CD30 Nodules-positive and ulcerating skin infiltrate tumors on left upper leg for 2 months. Diagnosis: transformed MF (CD30+)

CD3 CD30 CD3

35 DD. Diffuse CD30-positive skin infiltrate

Examination: nodules and ulcerating tumors on left upper leg for 2 months.

Histology: Diffuse CD30+ dermal infiltrate; DD: (C-)ALCL; transformed MF

Staging: no extracutaneous disease

Final diagnosis: MF with large cell transformation

Therapy: RT (tumor); topical steroids (patches)

Follow-up: nodal and pleura lesions 4 years after diagnosis. PCL vs nodal NHL -/+ secondary cutaneous involvement

Primary cutaneous lymphomas are visible and accessible: • Different types of CTCL and CBCL have a characteristic clinical presentation that may be helpful in diagnosis and classification. • Different types of cutaneous lymphoma can show an identical histology → classification on the basis of histology alone impossible. • Histologic diagnosis = differential diagnosis ≠ final diagnosis → clinicopathologic correlation essential • CTCL is not a diagnosis ! PCL vs nodal NHL -/+ secondary cutaneous involvement

MF C-ALCL LyP PCSM-TCLPD

Pc PTCL, NOS Aggressive CD8+ CTCL CGD-TCL Extranodal NK/T 5-year survival of different types of CTCL

90% 90% 99% 100%

MF C-ALCL LyP PCSM-TCLPD

<20% <20% <15% <15%

Pc PTCL, NOS Aggressive CD8+ CTCL CGD-TCL Extranodal NK/T PCL vs nodal NHL -/+ secondary cutaneous involvement

Primary cutaneous lymphomas are visible and accessible: • Different types of CTCL and CBCL have a characteristic clinical presentation that may be helpful in diagnosis and classification. • Different types of cutaneous lymphoma can show an identical histology → classification on the basis of histology alone impossible. • Histologic diagnosis = differential diagnosis ≠ final diagnosis → clinicopathologic correlation essential • CTCL is not a diagnosis → Do not use the term without further specification. PCL vs nodal NHL -/+ secondary cutaneous involvement

Primary cutaneous lymphomas are visible and accessible: • Different types of CTCL and CBCL have a characteristic clinical presentation that may be helpful in diagnosis and classification. • Different types of cutaneous lymphoma can show an identical histology → classification on the basis of histology alone impossible. • Histologic diagnosis = differential diagnosis ≠ final diagnosis → clinicopathologic correlation essential • CTCL is not a diagnosis → Do not use the term without further specification.

• Therapeutic consequences: importance of skin-directed therapes (topical steroids; topical cytostatics; phototherapy; radiotherapy). New concepts in cutaneous lymphoma classification

▪ Primary ≠ secondary cutaneous lymphomas. • Histologic diagnosis ≠ final diagnosis. • Clinical presentation (localization !!) major diagnostic adjunct. • Clinicopathologic correlation essential in diagnosis and classification

New types of CTCL and CBCL

New classifications (EORTC; WHO-EORTC; WHO-EORTC 2018) New types of CTCL and CBCL: 1985 - 1996

1987 primary cutaneous follicle center cell lymphoma 1989 primary cutaneous CD30+ large T-cell lymphoma (C-ALCL) vs 1989 primary cutaneous CD30 - large T-cell lymphoma 1991 primary cutaneous immunocytoma (PCMZL) 1992 spectrum primary cutaneous CD30+ LPD 1993 CD30-negative CTCL (non-MF) [small vs large] 1996 primary cutaneous large B-cell lymphoma of the leg

Should be, but were not included as distinct disease entities in malignant lymphoma

classifications to prevent unnecessarily aggressive treatment: → EORTC classification (1997) EORTC classification for cutaneous lymphomas

Cutaneous T-cell Lymphoma Cutaneous B-cell Lymphoma

Indolent behaviour Indolent behaviour • Mycosis fungoides • Follicular MF • follicle center cell lymphoma • Pagetoid reticulosis • marginal zone B-cell lymphoma/ • Lymphomatoid papulois immunocytoma • CTCL, large cell (CD30+)

Aggressive behaviour Intermediate behaviour • Sezary syndrome • large B-cell lymphoma of the leg • CTCL, large cell (CD30-)

Provisional entities Provisional entities • granulomatous slack skin • plasmacytoma • CTCL, pleomorphic small/medium • intravascular large B-cell lymphoma • subcutaneous panniculitis-like T-cell lymphoma

Willemze R et al: BLOOD 1997;90: 354-371 EORTC classification for cutaneous lymphomas

• First classification for primary cutaneous lymphomas.

• Recognition of distinct disease entities.

• Distinction between indolent, intermediate and aggressive types of CTCL and CBCL.

• Clinical relevance validated on more than 1300 patients.

• Reluctance among hematopathologists to accept organ specific classifications. WHO-EORTC classification for cutaneous lymphomas 2005

➢ Classification for primary cutaneous lymphomas. ➢ Not widely used by hematopatholopgists and hematologists

Willemze R. et al, Blood 2005; 105: 3768-3785 Classification of primary cutaneous lymphomas

Classification DER PA HEM

1988 Updated Kiel classification - (+) + 1997 ESDR classification + (+) -

rd - + + 2001 WHO classification (3 edition) WHO 2016 2005 WHO-EORTC classification + (+) - 2008 WHO classification (4th edition) + + + 2016 WHO classification (revised 4th ed.) + + + 2018 update WHO-EORTC classification + + +

WHO-EORTC 2018 Classification of primary cutaneous lymphomas

Treatment PCFCL and Classification DER PA HEM C-ALCL with RT

1988 Updated Kiel classification (+) - - 1997 ESDR classification + (+) - - 2001 WHO classification (3rd edition) - + + - 2005 WHO-EORTC classification + (+) - - 2008 WHO classification (4th edition) + + + + 2016 WHO classification (revised 4th ed.) + + + + 2018 update WHO-EORTC classification + + + + 2018 update of the WHO-EORTC classification

Cutaneous T-cell lymphomas Cutaneous B-cell lymphomas • Mycosis fungoides & variants of MF – Folliculotropic MF • Primary cutaneous marginal zone lymphoma – Granulomatous slack skin • Primary cutaneous follicle center lymphoma – Pagetoid reticulosis • Primary cutaneous DLBCL, leg type • Sezary syndrome • EBV-positive mucocutaneous ulcer • Spectrum cutaneous CD30+ LPD • Intravascular large B-cell lymphoma • Subcutaneous panniculitis-like T-cell lymphoma • Extranodal NK/T-cell lymphoma • Hydroa vacciniforme-like LPD (CAEBVI) • Primary cutaneous peripheral T-cell lymphoma, NOS + rare subtypes - Primary cutaneous γ/δ T-cell lymphoma - Aggressive cytotoxic epidermotropic CD8+ CTCL - Primary cutaneous CD4+ small/medium T-cell LPD - Primary cutaneous acral CD8+ T-cell lymphoma 2017

2018 Blood 2019;133:1703-1714 2018 update of the WHO-EORTC classification

75%

25%

Willemze R. et al; Blood 2019;133:1703-1714 Summary

• Cutaneous lymphomas: heterogeneous group of rare diseases • CTCL (75%) much more common than CBCL (25%) • CTCL is not a diagnosis, but refers to a group of diseases with different treatment and prognosis. • Histopathologic diagnosis ≠ final diagnosis. • Cutaneous lymphomas are defined by a combination of histological, phenotypical, genetic and clinical criteria (clinicopathologic entities). • Clinical presentation (localization !!) often is a major diagnostic adjunct. • If the clinician fails to provide the appropriate clinical information, a definite diagnosis can often not be made. Take-home message

Clinicopathologic correlation and a multidisciplinary approach form the basis of cutaneous lymphoma diagnosis and classification and are a prerequisite for correct management and treatment. Cutaneous Lymphoma Webinars

• Introduction to Cutaneous Lymphoma: Rein Willemze

• Mycosis Fungoides: Maarten Vermeer

• Sézary Syndrome: Martine Bagot & Pietro Quaglino

• CD30+lymphoproliferations: Werner Kempf

• Aggressive T-cell lymphomas: Pietro Quaglino & Evangelia Papadavid

• Indolent CBCL (PCFCL and PCMZL): Pablo Ortiz & Emmanuella Guenova

• Aggressive CBCL (PCDLBCL-LT): Marie Beylot Barry & Anne Pham-Ledard

• New therapeutic developments I: Julia Scarisbrick

• New therapeutic developments II: Rudolf Stadler Discussion