23 Novembre 2011

Martine BagotDepartment of Dermatology and Inserm U976, Hôpital Saint-Louis, Paris, France

martine.bagot@sls.aphp.fr

Signes cutanSignes cutanéés des Leucs des Leucéémiesmies

Recognizing skin manifestations of

hematooncologic diseases is

important for the:

Introduction

• Early diagnosis of

hematooncological neoplasms/

relapses

• Prognosis of the disease

Skin manifestations of hematooncologic

disorders can be classified as:

1. Specific lesions (excluding primary cutaneous lymphomas)

2. Associated / paraneoplastic lesions

Introduction

= Leukaemia cutis --> skin lesions due to infiltration of

leukemic cells

1. Myeloid leukaemia cutis

mainly AML M4/5 (>50% of cases)

less frequently: AML M1/3, CML, myelodysplastic disorders

Ø Worsening of the prognosis

Ø Leukemia cutis may be first symptom

in ~ 5 % of AML patients

Ø therapeutic challenge!

2. Lymphoid leukaemia cutismainly CLL, rarely ALL

1. Specific skin lesions

Papules, plaques, tumors, sometimes hemorragic

• Hyperplasia of oral mucosa

• In AML, oral cavity is frequently early involvedØ 80% of AML patients (M4, M5)

• Often the first symptom of disease!

Specific lesions in myeloid hemopathies

Chronic myelomonocytic leukemia

Specific lesions in myeloid hemopathies

Plasmacytoid dendritic cell neoplasm

Specific lesions in myeloid hemopathies

Plasmacytoid dendritic cell neoplasm

Specific lesions in myeloid hemopathies

CD123

• Difficult to diagnose (histology)

• More abundant in myelodysplastic syndrome (frequently a sign of transformation in acute leukemia)

Ø blisters

Ø necrotic lesions

Ø subcutaneous nodules

Ø prurigo

Ø ecchymoses

Myeloid haemopathies: atypical specific skin lesions

Histologic and Immunohistologic Characterization of Skin Localization of Myeloid Disorders. A Study of 173 Cases

Am J Clin Pathol 2011;135:278-290C Bénet, A Gomez, C Aguilar, C Delattre, B Vergier, M Beylot-Barry, S Fraitag, A Carlotti, P Dechelotte,V Hospital, M d’Incan,V Costes,O Dereure, N Ortonne, M Bagot, L Laroche, A Blom, S Dalac, and T Petrella

Types:

• Angioimmunoblastic T-cell lymphoma

(Angioimmunoblastic lymphadenopathy with dysproteinemia; AILD)

• HTLV-1 Leukemic Lymphoma

• CLL: Specific and insect-bite like reactions

• Intravascular B-cell lymphoma

Specific skin lesions in lymphoid hemopathies

1. Angioimmunoblastic T-cell Lymphoma(Angioimmunoblastic Lymphadenopathy with Dysproteinemie: AILD)

Lymphoid Hemopathies: Specific skin lesions

• Febrile, maculo-papular eruption(DD: adverse cutaneous drug eruption)

• Lymphadenopathy, polyclonalhypergammaglobulinemia, hepatosplenomegaly

• Skin lesions in 40% of cases

• Precedes diagnosis of thehemopathy in 30% of cases

1. Angioimmunoblastic T-cell Lymphoma

Lymphoid Hemopathies: Specific skin lesions

CXCL13CD10

1. Angioimmunoblastic T-cell Lymphoma

Lymphoid Hemopathies: Specific skin lesions

1. Angioimmunoblastic T-cell LymphomaIgA linear dermatosis

Lymphoid Hemopathies: Specific skin lesions

2. Leukemic HTLV-1 Lymphoma:

§ Adult T cell leukemia/lymphoma (ATLL)

§ 60% of cases --> skin involvement

§ Diffuse red-brown papulo-nodular skin

eruption

§ Erythroderma possible

Lymphoid Hemopathies: Specific skin lesions

3. Chronic lymphocytic leukemia

Lymphoid Hemopathies: Specific skin lesions

3. Chronic lymphocytic leukemia

Insect-like bite reactions

Lymphoid Hemopathies: Specific skin lesions

4. Intravascular B-cell lymphoma

Lymphoid Hemopathies: Specific skin lesions

Plan

Skin manifestations of haematooncologic

disorders can be classified as:

1. Specific lesions (excluding primary cutaneous lymphomas)

2. Associated/paraneoplastic lesions

1. Neutrophilic dermatosesSweet-Syndrome AMLPyoderma gangraenosum IgA Myeloma, MyelodysplasiaErythema elevatum et diutinum IgA Myeloma, MyelodysplasiaSneddon-Wilkinson Syndrome IgA Myeloma, Lymphoid leukemiaNeutrophilic eccrine Hidradenitis AML

2. Vascular manifestation LivedoErythromelalgiaVasculitisSuperficial Phlebitis (Phlebitis saltans)Cryoglobulinaemia

3. Lesions via Ig deposition AmyloidosisMacroglobulinaemia (M. Waldenström)Acral follicular hyperkeratosis

4. Lesions via mAb Activity of Ig Necrobiotic XanthogranulomaXanthoma planumSchitzler syndrome Paraneoplastic Pemphigus

5. Varia ScleromyxedemaUrticariaPruritus/Prurigo Erythema nodosumPOEMS Syndrome

Associated/paraneoplastic skin lesions

Ø 8-13 % of Sweet-Syndrome cases associated with a hemopathy

Ø 11% of cases precede the diagnose of the hemopathy

Ø Usual clinical presentation but:

Ø More often bullous (75% of cases)

Ø More often on arms (94% of cases)

1. Neutrophilic Dermatoses: Sweet-Syndrome

Clinical signs:

Ø Livid red papules-nodules

Ø Irregular surface (mountainous..)

Ø Fever > 38°C, elevated CRP

Ø Leucocytosis with neutrophilia (> 70%)

1. Neutrophilic Dermatoses: Pyoderma gangrenosum

Ø Associated with: Myeloma (IgA), Myeloid Leukemias,

Polyglobuly, Thrombocytosis, Myelofibrosis

Ø No specific clinical presentation

(Bullous variant more frequent ?)

Ø Disseminated form often associated

with IgA Paraproteinemia

Clinical signs:

Ø Centrifugally developing painful andnecrotic ulcer(s)

Ø Livid red and undermined border

1. Neutrophilic Dermatoses: Erythema elevatum et diutinum

Associated with:

Ø Myeloid hemopathies in 46 % of cases

Ø also often with IgA Myeloma

Clinical signs:

Ø Bright-livid red papules, nodules, plaques

Ø Flat surface, depressed center

Ø Disseminated or aggregated

Ø Extensor surfaces of extremities(feet, knees, hands)

Ø Pustulosis subcornealis

Ø In contrast to other neutrophilic dermatoses

à connection with lymphoid disorders

à frequently IgA Gammopathies (benign/MM)

1. Neutrophilic Dermatoses: Sneddon-Wilkinson-Syndrome

Clinical signs:

Ø Superficial small-large pustules withinflammatory borders

Ø Circinar-polycyclic erosions, collerette scales

Ø Symmetric on trunk, proximal extremities, body folds

1. Neutrophilic Dermatoses: Neutrophilic eccrine hidradenitis

Ø Almost exclusively associated with AML

Ø Development frequent during post-chemotherapy aplasia

(Anthracycline, Cytarabine, Cyclophosphamide, Sorafenib, Imatinib)

Ø Rarely precedes hematologic disorders

Clinical signs:

Ø Similar to Sweet syndrome, but location on eccrine sweat gland areas,

Ø Painful papules and nodules, plaques

Ø Palmoplantar, axilla, extremities, face/neck (periorbital)

1. Neutrophilic dermatoses Sweet-SyndromPyoderma gangraenosumErythema elevatum et diutinumSneddon-Wilkinson SyndromNeutrophilic eccrineHidradenitis

2. Vascular manifestationLivedo Myelodysplasia, M. WaldenströmErythromelalgia Myelodysplasia, CMLVasculitis Myelodysplasia, hairy cell leukemiaSuperficial Phlebitis Acute leukemia (Adenocarcinoma) Cryoglobulinaemia Multiple Myeloma, M. Waldenström

3. Lesions via Ig deposition AmyloidosisMacroglobulinaemia (M. Waldenström)Acral follicular hyperkeratosis

4. Lesions via mAb Activity of Ig Necrobiotic XanthogranulomaXanthoma planumSchnitzler syndrome Paraneoplastic Pemphigus

5. Varia ScleromyxedemaUrticariaPruritus/Prurigo Erythema nodosumPOEMS Syndrome

Associated/paraneoplastic skin lesions

Mainly in myeloid hemopathies (myelodysplasia)

• Livedo: Polycythemia, Thrombocythemia,Waldenströms disease

• Erythromelalgy: Polycythemia (30%), Thrombocythemia, CML

2. Vascular manifestations:

Clinical signs:

Ø Increased sensitivity towards heat

Ø Hyperaemia, erythema, swelling

Ø Burning sensation

Ø Increased skin temperature

Ø Hyperhidrosis (or Hypo-/Anhidrosis)

• Vasculitis: rare

Ø 2 Types:

Ø Infiltrated purpura (Histo: leucocytoclastic vasculitis)

Ø Periarteritis Nodosa-like nodular subcutaneous skin lesions(Histo: granulomatous vasculitis)

ØAppear often before the diagnosis of hemopathy

Ø Tricholeucocytic leukemia

Ø Myelodysplastic syndrome

Ø Drug or Infections (Mycobacteria) in immunsuppressed patients may be a confounding factor

2. Vascular manifestations:

• Superficial phlebitis: in 6% of polyglobuly patients

• Cryoglobulinemia:

ØType I:

= Monoclonal (usually IgG or IgM)

ØAssociation with B-cell proliferations

Ø Myeloma

Ø Waldenström

Clinic: acrocyanosis, vascular occlusion +

ulcer(s), purpura induced by cold, ecchymosis,

acral hyperpigmentation

2. Vascular manifestations:

1. Neutrophilic dermatoses Sweet-SyndromPyoderma gangraenosumErythema elevatum et diutinumSneddon-Wilkinson SyndromNeutrophilic eccrineHidradenitis

2. Vascular manifestation LivedoErythromelalgieVasculitisSuperficial Phlebitis Cryoglobulinaemia

3. Lesions via Immunoglobulin depositionAmyloidosis Multiple Myeloma, M. WaldenströmMacroglobulinaemia M. WaldenströmAcral follicular hyperkeratosis Multiple Myeloma

4. Lesions via mAb Activity of Ig Necrobiotic XanthogranulomaXanthoma planumSchnitzler syndrome Paraneoplastic Pemphigus

5. Varia ScleromyxedemaUrticariaPruritus/Prurigo Erythema nodosumPOEMS Syndrome

Associated/paraneoplastic skin lesions

Associated with B-cell hemopathies

a. Amyloidosis: most frequent

ØAL Type systemic amyloidosis

Ø Clinical signs:

Ø Purpura (face-eyelids, folds)

ØMacroglossia (painful)

Ø Papules-nodules (whitish or yellowish)

ØHisto: Dermal amyloid deposits

3. Lesions due to Ig deposition:

b. Macroglobulinemia:Ø In Waldenström’s disease

(Plasmocyte proliferation withmonoclonal IgM production)

ØClinic:

Ø Mucosal bleeding (mouth/nose), CNS, retina..

Ø Characteristic symmetrical pinkpapules/nodules often with petechiae --> face, ears

c. Acral follicular spicules:Ø IgG deposits in follicular

ostium of myeloma patients

3. Lesions due to Ig deposition:

1. Neutrophilic dermatoses Sweet-SyndromPyoderma gangraenosumErythema elevatum et diutinumSneddon-Wilkinson SyndromNeutrophilic eccrineHidradenitis

2. Vascular manifestation LivedoErythromelalgiaVasculitisSuperficial Phlebitis Cryoglobulinaemia

3. Lesions via Ig deposition AmyloidosisMacroglobulinaemia (M. Waldenström)Acral follicular spicules

4. Lesions via mAb Activity of ImmunoglobulinsNecrobiotic Xanthogranuloma Multiple myelomaXanthoma planum Multiple myelomaSchnitzler syndrome M. WaldenströmParaneoplastic Pemphigus M. Castleman, Myeloma

5. Varia ScleromyxedemaUrticariaPruritus/Prurigo Erythema nodosumPOEMS Syndrome

Associated/paraneoplastic skin lesions

4. Lesions caused by mAb activity of Iga. Necrobiotic xanthogranuloma

Ø Rare disease

Ø 90% of cases associated with monoclonal IgG k oder lparaprotein, 40% cryoglobulinemia

Clinical signs:

Ø Red-orange to violet papules --> sharply delimited plaques withxanthomatous aspect

Ø Frequent central ulceration or atrophy with telangiectasias

Ø Localisation: 85% periorbital, alsotrunk, extremities, mouth

4. Lesions caused by mAb activity of Iga. Necrobiotic xanthogranuloma

Ø Pathogenesis and treatment of xanthomatosis associatedwith monoclonal gammopathy

Blood 2011 Oct 6;118(14):3777-84

CD163

b. Xanthoma planumØ Multiple myeloma:

monoclonal Ig-lipoprotein complex

Ø Tissue deposition and consecutivemacrophage activation

c. Schnitzler syndromeØ Urticaria, fixed, little pruritus

Ø Arthralgias & bone pain

Ø Recurrent fever bouts

Ø Monoclonal IgM

--> Interleukin 1b activity, therapy: Anakinra (IL1Ra-Fc)

4. Lesions caused by mAb activity of Ig

d. Paraneoplastic pemphigusPNP pemphigus due to NK/T cell lymphoma, Br J Haematol 2011 Presse Med, 2010

4. Lesions caused by mAb activity of Ig

e. Generalized acquired cutis laxa• Myeloma

• Granuloma annulare plaque

• Immunologic destruction of elastic fibers

4. Lesions caused by mAb activity of Ig

Douglas New, Arch Dermatol 2011

1. Neutrophilic dermatoses Sweet-SyndromPyoderma gangraenosumErythema elevatum et diutinumSneddon-Wilkinson SyndromNeutrophilic eccrineHidradenitis

2. Vascular manifestation LivedoErythromelalgiaVasculitisSuperficial Phlebitis Cryoglobulinaemia

3. Lesions via Ig deposition AmyloidosisMacroglobulinaemia (M. Waldenström)Acral follicular hyperkeratosis

4. Lesions via mAb Activity of Ig Necrobiotic XanthogranulomaXanthoma planumSchnitzler syndrome Paraneoplastic Pemphigus

5. VariaScleromyxedema Multiple MyelomaUrticaria variousPruritus/Prurigo M. Hodgkin, various Erythema nodosum M. HodgkinPOEMS Syndrome Multiple myeloma

Associated/paraneoplastic skin lesions

5. Varia: Scleromyxedema

Ø Most cases associated with monoclonal IgGparaproteinaemia of the l light chain type

Ø Association with multiple myeloma or Waldenström

Clinical signs:

Ø Upper thoracic area with thickenedskin

Ø Solitary solid skin-coloured papules --> neck & frontal regions

Ø Reduced mobility (sclerodermiform)

5. Varia: Scleromyxedema

5. Varia: Scleromyxedema

5. Varia: Scleromyxedema

5. Varia: POEMS Syndrome

Polyneuropathy (peripheral sensomotoric disturbances)

Organomegaly (Hepatosplenomegaly, Lymphadenopathy)

Endocrinopathy

Monoclonal Gammopathy

Skin Alteration:

Ø Hyperpigmentation (77%)

Ø Sclerodermiform alterations (60%)

Ø Hypertrichosis (50%)

Ø Haemangioma (Histo: glomeruloid)

Ø Leukonychia (20%)

+ overproduction of IL 1, IL 6, TNF

Summary

There are specific and associated skin signs ofhaematooncologic disorders.

We have to recognize them, as they

• May allow earlier diagnosis and better treatment

• Can be predictive for prognosis

Dermatological exam and Biopsy