Case 38, 2007-Gen Painful Ulcersted Lesions

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Clinicopathologic Conference

HMS Dermatopathology Course

October 20, 2006Vincent Liu, M.D.

Dermatology and DematopathologyUniversity of Iowa School of Medicine

Iowa City, IAAlison Z. Young, M.D., Ph.D.Dermatology

Virginia Mason Medical CenterSeattle, WA



HPI #1/11: Original Lesions,

2.3 years prior to admission• Erosions on scalpdeveloped soon after

beginning sumatriptin for headaches

• Subsequent diffuse scaly erythematouspapules and plaquesover the rest of the

body, resistant to topical steroid and

cephalexin



HPI #2/11: Outside

Dermatology Evaluation• Scarring alopeciaand multiple hyperkeratotic

erythematous plaqueson the trunk and arms

• Pathology of hyperkeratotic plaque: hypertrophic

lichenoid dermatitis with eosinophilia• Bloodwork: leukocytosis (13.6K) with negative ANA

• Topical and systemic corticosteroids andhydroxychloroquine-> some improvement

• Three months later, topical tacrolimusand cephalexin

course• Psoralen-UVA photochemotherapy

• 23 months prior to admission, erythematous lesionsaroseon face and left lower eyelid



HPI #3/11: Initial Presentation to

MGH Clinic (14 months PTA)• Tender 3-6 cm plaquesand nodulesover

face, trunk, and extremities, some eroded,

appearing lichenoid to hypertrophic toverrucous

• Bloodwork: rheumatologic serologiesnegative

• Treatment: topical tacrolimus andclobetasol cream









HPI #4/11: Squamous Cell

Carcinoma-like Lesions• Biopsy of verrucous lesion on right thigh: well-

differentiated invasive squamous cell carcinoma

• Left lower leg lesion removed by Mohs surgery

three weeks later, revealing well-differentiatedinvasive squamous cell carcinoma

• Treatment: isotretinoin (20 mg daily)

• On follow-up (10 months PTA) boggy,

erythematous, irregular thin plaquein the leftinframammary area and an oozing, crusted lesion over the left lateral deltoid seen, treated withtopical mupirocin



HPI #5/11: Hospital Admission #1

(8 months PTA)• Admitted through the ER for increased frequency of

palpitations and anxiety• CT scan: no PE or DVT, and bilateral axillary and

mediastinal lymph nodes at upper range of normal• Ophthalmology consult: left periorbital swelling anderythema, ectropion, lagophthalmos, and exposurekeratopathy, with positive Schirmer test bilaterally

• Rheumatology consult: no synovitis, myositis, or

acrosclerosis• Flow cytometry of peripheral blood: polyclonal B cells,normal T cells, normal CD4+:CD8+ ratio

• Isotretinoin increased to 40 mg daily



HPI #6/11: Evolution of Lesions

• New lesion on right lower abdomen: squamous cellcarcinoma

• New England Dermatological Society discussion: eruptive

keratoacanthomaversus squamous cell carcinomaversusverrucous carcinomaversus hypertrophic lichen planus versus lupus erythematosus

• Previous biopsy specimen testing: negativefor HPV

• Superinfection of lesions by Staphylococcus aureus,treated with cephalexin and tetracycline

• Mycophenolate mofetil begun (3 months PTA);isotretinoin discontinued



HPI #7/11: Hospitalization #2

(2-3 months PTA)• Some improvement noted two weeks after

mycophenolate begun, but then new

annular erythematous painful lesionswithnecrotic black central ulcerations developed

• Readmission to hospital







HPI #8/11: Evaluation on

Admission• Morphology: Painful erythematous targetand reniform

lesionswith central ulceration

• Distribution: chest, abdomen, back, bilateral arms, right

leg• Pleomorphism: varying stages of evolution – erythematous nodules

– lesions with central clearing – lesions with necrotic ulceration

• Distinction: from the original hyperkeratotic nodules onthe legs with minimal involvement of the scalp, palms, andsoles

• Associated finding: Left periorbital edema and erythema




Work-up• CT scan chest/abdomen/pelvis: extensive bilateral axillary

and inguinal lymphadenopathy

• Skin biopsy, abdomen: acute spongiotic dermatitis with

numerous eosinophils, suggestive of a drug eruption • Cultures, skin: Staph aureus, Pseudomonas aeruginosa

• Treatment:

– Discontinuation of mycophenolate mofetil

– Levofloxacinbegun – Prednisonetaper

– Morphinepain control



HPI #10/11: Third rash

(1 month PTA)• Ten days later, new blanching erythematous

lesionsbetween target lesions on trunk andextremities: diagnosed as levofloxacin

hypersensitivity • Treatment: discontinued levofloxacin; started

topical mupirocin

• Response:

– Some of the ulcerated lesions flattened and crustedover, but most persisted

– Pain required narcotic analgesia

– Hair & nail testing negative for arsenic




• Three weeks after discharge, fever (38

degrees F), purulent drainagefrom lesions

on the right foot and left axilla – Culture: S. aureus, P. aeruginosa

– Treatment: topical mupirocin

• Readmittedwith persistent fever



Past Medical History

• Eczemaat age 24, generalized but sparing

face, with winter exacerbation, treated with

topical steroids and tacrolimus• Migraineheadaches, treated with

sumatriptan

• History of one miscarriage



Social History

• Worked as secretary, currently on disability

• Married with children, lived with husband

• Smoked 1-1/2 packs daily; rare alcohol

• Traveled throughout Eastern U.S.

• Drank well water in childhood



Family History

• Mother died of lung cancer

• Father’s history unknown



Allergies and Medications

• Allergy to penicillin• Medications on Admission

– Prednisone

– Oxycodone – Morphine sulfate

– Lorazepam

– Zinc

– Citalopram

– Alendronate

– Gabapentin

– Erythromycin gel

– Mupirocin



Physical Examination

• General: awake, alert, tearful

• Vitals: febrile (T 38), tachycardic (105 bpm), bpWNL, resp WNL

• Skin:• Generalized, confluent annular ulcerated plaques, covering

>60-70% BSA

• Multiple 0.5-cm hyperkeratotic papules, predominantly onlegs

• Erosions and deep ulcerationson right neck, right breast, rightheel with green discharge

• Left periorbital swellingand erythema

• 2+ edemabilateral lower legs



Laboratory Tests

• CBC: anemia (Hct 31); leukocytosis (16.8) with left shift(93% neuts); thrombocytosis (733K)

• Chemistry panel: WNL

• LFTs: WNL

• ANA: positive at 14 months prior to admission (1:640speckled); positive anti-U1 sn-RNP

• T-cell subsets: normal CD4:CD8 ratio (4 mos PTA)

• SPEP: abnormal pattern- v. low conc’n bands in gammaregion, IgG kappa M components (4 mos PTA)



Clinical Summary

• 44 year old Caucasian woman – 2.3-year history of generalized hyperkeratotic verrucous

papulonodules – admitted for fever and purulent drainagefrom ulcerated annular

plaquesand tumorsfor the past 2 months – following an episode of presumed levofloxacin cutaneous

hypersensitivity – with work-up to date notable for skin pathology interpreted as

squamous cell carcinomaand laboratory tests showing a positiveANA, positive anti-U1 snRNP, anemia, leukocytosis with a left

shift, and thrombocytosis – and minimal improvement to treatment with topical and systemic

steroids, topical tacrolimus, systemic hydroxychloroquine, PUVA,oral antibiotics, isotretinoin, and mycophenolate



Questions: Challenge to

Differential Diagnosis• Do all the patient’s cutaneous manifestations reflect the

same process (Occam’s razor )?

• If there are multiple processes, is there causalityin the

association? (What is primary and what is secondary?)• What is the true nature of the biopsies interpreted as

squamous cell carcinoma? (Could there be an element of pseudoepitheliomatous hyperplasia?)

• What is the role of the patient’s history of “eczema”? • What is the role, if any, of medication-induced

immunosuppression in the pathogenesis?



Goals

• To review the remarkably varied clinical

differential diagnosisfor disseminated

ulcerated, verrucous, plaques• To use the clinical and reported pathologic

data to arrive at a most likely diagnosis

• To try to account for the apparentlyevolving morphologyof the lesions



Goals








Differential Diagnosis:

Disseminated verrucouspapulonodules

??????




Disseminated verrucouspapulonodules

• Disseminated squamous cell carcinomas



Disseminated Squamous Cell

Carcinomas: Clinical Settings• Sun-exposed• Scars (Marjolin’s)

– Trauma

– Burns

– Frostbite – Vaccination scars

– Pyoderma gangrenosum

• Underlying conditions – Dystrophic epidermolysis bullosa

– Hailey-Hailey disease

– Porokeratosis

– Discoid lupus erythematosus

– Lichen planus

• Immunosuppression- organ transplant recipients



Squamous Cell Carcinomas:

Clinical




Clinical



Disseminated Squamous Cell

Carcinomas: Pathology• Architecture:

– Nests of atypical squamous epithelium arising from the

epidermis and extending into the dermis

– Foci of keratinization

• Cytomorphology:

– Eosinophilic cytoplasm

– Nuclear pleomorphism and hyperchromasia

– Mitoses

– Dyskeratosis




Pathology





Disseminated verrucous

papulonodules• Disseminated squamous cell carcinomas – Multiple keratoacanthomas



Multiple Keratoacanthomas:

Clinical• Types

– Ferguson-Smith (hereditary, self-healing)

– Grzybowski (eruptive)

– Mixed (overlap features) – Localized (one side or area of body)

– Sites of trauma

– Sites of underlying dermatosis

– Muir-Torre syndrome• Associations – Visceral malignancy (GI tract) in Muir-Torre syndrome



Keratoacanthoma: Pathology

• Architecture:

– Crateriform, exoendophytic, keratinizing squamous

proliferation

– Central keratinous material

– Peripheral buttressing of edges

• Cytomorphology:

– Cellular enlargement

– Eosinophilic cytoplasm with “glassy” appearance



Keratoacanthoma: Clinical



Keratoacanthoma: Pathology



Multiple Keratoacanthomas as

Paraneoplastic Phenomenon?

Muir-Torre Syndrome• Familial cancer syndrome

• At least one sebaceous neoplasm – Adenoma

– Epithelioma

– Carcinoma

• At least one visceral malignancy – Gastrointestinal- hereditary nonpolyposis colorectal cancer syndrome

– Genitourinary tract tumors

– Breast carcinoma

– Lymphoma/leukemia• Other cutaneous neoplasms

– Keratoacanthomas – Squamous cell carcinomas – Multiple follicular cysts

• MSH2 gene mutation






papulonodules• Disseminated squamous cell carcinomas – Multiple keratoacanthomas – Verrucous carcinomas



Verrucous Carcinomas: Clinical

• Location:

– Oral cavity

– Larynx – Esophagus

– Skin (plantar)

• Setting:

– Environmental carcinogen (tobacco, betel)

– HPV implicated (6, 11, 16, 18)



Verrucous Carcinoma: Clinical



Verrucous Carcinomas: Pathology

• Architecture:

– Exoendophytic papillomatous squamous proliferation

– Hyperparakeratosis

– Bulbous expansion of rete pegs (blunted, rather than jagged)

– Burrows and draining sinuses (epitheliomacuniculatum)

• Cytomorphology: – Well-differentiated squamous epithelial cells

– Low mitotic activity



Verrucous Carcinoma: Pathology



Pseudoepitheliomatous

Hyperplasia: Pathology



Pseudoepitheliomatous

Hyperplasia:

Pathologic Differential Diagnosis• Inflammatory

– Chronic irritation• Peristomal

• Trauma• Cryotherapy

• Chronic lymphedema

– Infections• Chromomycosis

• Sporotrichosis

• Aspergillosis

• Pyoderma

• Actinomycosis

• Chronic verrucous lesions inimmunocompromised patientswith HSV/VZV

– Dermal inflammatory processes• Halogenodermas

• Chondrodermatitis nodularishelicis

• Neoplastic – Spitz nevi

– Malignant melanoma

– Granular cell tumor – Cutaneous T-cell lymphoma







• Variant of lupus erythematosus

– Hypertrophic variant – Lichen planus/lupus erythematosus overlap

• Disseminated infection – Mycoses



Mycoses: Clinical

• Systemic Mycoses – Coccidiodomycosis

– Blastomycosis

– Histoplasmosis – Cryptococcosis

– Paracoccidiodomycosis

• Dematiaceous Fungal Infections

– Chromomycosis – Phaeohyphomycosis

• Sporotrichosis



Systemic Mycoses:

Coccidiodomycosis• Clinical

– Acute self-limited pulmonary infection

– U.S. Southwest, Mexico, Central & South America

– Dissemination in immunocompromised – Verrucous plaques, subcutaneous abscesses, pustules, ulceration

– Erythema nodosum

• Pathological

– Pseudoepitheliomatous hyperplasia

– Non-caseating granulomas in the upper and mid dermis

– Thick-walled spherules (10-80 microns) within multinulceate giantcells

– Endospores within spherules (sporangia)



Systemic Mycoses: Blastomycosis

• Clinical – Three forms:

• Pulmonary

• Disseminated

• Primary cutaneous

– North America, Africa, India

– Crusted verrucous noduleor ulcerated plaque, widespread pustules, esp.face

• Pathological – Pseudoepitheliomatous hyperplasia

– Polymorphous dermal inflammatory infiltrate with giant cells

– Microabscesses

– Poorly formed granulomas

– Thick-walled yeasts (7-15 microns) with broad based budding within giantcells



Systemic Mycoses: Histoplasmosis

• Clinical – America, Africa, Asia

– Dimorphic soil fungus

– Lung is primary focus

– Immunosuppression predisposes to dissemination, with skin involved in5%

– Papules, ulcerated nodules, cellulitis-like areas, acneiform lesions, or erythroderma

– Erythema nodosum

• Pathological

– Pseudoepitheliomatous hyperplasia – Granulomatous inflammation of dermis into subcutis

– Parasitized macrophages

– Small ovoid yeast-like organisms (2-3 x 3-5 microns) with surroundingclear halo



Dematiaceous Mycoses:

Sporotrichosis• Clinical

– Inoculation into skin with trauma

– Ulcerative, verrucous, acneiform, erythematous lesions

• Pathological – Pseudoepitheliomatous hyperplasia

– Suppurative granulomas with concentric zones• Neutrophilic microabscess centrally

• Cuff of epithelioid and multinucleated histiocytes

• Outer cuff of lymphoplasmacytic infiltrate

– Round or oval (4-6 micron) organisms uncommon withasteroid bodies









• Disseminated infection – Mycoses – Mycobacterial infection



Mycobacterial Infection: Clinical

Multiple Squamous Cell



p q

Carcinomas/Keratoacanthomas/

Verrucous Carcinomas: J udgment• Pros

– Pathology suggestive – Multiple lesions

documented

• Cons

– No clear underlyingassociation in this case

– No classic (GI/GU)malignancy

– No significant response

to systemic retinoids – Generalized

distribution

– Negative HPV testing




g







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– Hypertrophic variant



Lupus Erythematosus,

Hypertrophic Variant: Pathology• Epidermis

– Hyperkeratosis

– Verruciform epidermal hyperplasia

– Follicular plugging

– Dermal-epidermal junction vacuolar interface dermatitis

– Thickened basement membrane zone

• Dermis:

– Superficial and deep perivascular and periadnexal lymphocyticinflammation

– Mucin deposition

– Transepidermal elimination of elastotic material



Lupus Erythematosus: Pathology




Hypertrophic Variant: Pathology




g





H pertrophic Lichen



Hypertrophic Lichen

Planus/Lupus Erythematosus

Overlap: Clinical• Generalized verrucous skin-colored to

erythematous plaques distributed in a

generalized fashion with photodistributed

predilection



Hypertrophic Lichen Planus:

Clinical

Hypertrophic Lichen



Hypertrophic Lichen

Planus/Lupus Erythematosus

Overlap: Pathology• Verruciform papillomatous hyperplasia with

brisk lichenoid lymphocytic inflammation



Lupus Erythematosus Variant:

J udgment• Pros

– Positive serologies

(ANA, anti-U1snRNP)

– Reports of squamous

cell carcinoma

development inhypertrophic lupus

erythematosus

• Cons

– Lacks other ARA

criteria for lupuserythematosus

– Generalized

distribution and density

of lesions unusual




g





• Disseminated infection



Infectious: Categories

• Mycoses – Systemic

• Coccidiodomycosis

• Blastomycosis

• Histoplasmosis

• Cryptococcosis

• Paracoccidiodomycosis (in AIDS)

– Dematiaceous• Chromomycosis

• Sporotrichosis

• Mycobacterial – Lepromatous leprosy

– Atypical mycobacterial• Treponemal

– Yaws

– Bejel

• Leishmanial




Hypertrophic Variant: Clinical• Discoid lupus erythematosus lesions with

verrucous, hypertrophicmorphology

• Disseminated lesions

– cutaneous LE

– systemic LE

• Photodistribution (face and arms)

• More recalcitrant to therapy



Lupus Erythematosus: Clinical




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• Disseminated infection – Mycoses – Mycobacterial infection – Treponemal infection



Treponemal Infection, Yaws:

Clinical• Clinical – Primary: mother yaw enlarges, crusts, forms satellite pustules

– Secondary: systemic involvement of musculoskeletal and CNS withdaughter yaws and morbilliform eruption

– Tertiary: bone, joint, soft tissue deformity

• Pathological – Epidermis

• Acanthosis

• Papillomatosis

• Spongiosis

• Neutrophilic exocytosis – Dermis

• Diffuse infiltrate of plasma cells, lymphocytes, histiocytes, andgranulocytes

• No endothelial swelling

• Resemble condylomata lata

– Spirochetes between keratinocytes



Treponemal Infection, Yaws:

Pathology• Papillomatous epidermal hyperplasia,

spongiosis

• Intraepidermal microabscesses• Treponemes in epidermis








• Disseminated infection – Mycoses – Mycobacterial infection – Treponemal infection – Leishmanial infection



Leishmanial Infection: Clinical

• Protozoa transmitted by sandfly (“Baghdad boil”)

• Three types – Cutaneous

– Mucocutaneous

– Visceral (“kala azar”)

• Morphology: crusted, ulcerated papules;may have sporotrichoid spread



Leishmanial Infection: Pathology

• Irregular acanthosis

• Mixed infiltrate, vaguely granulomatous

• Intracellular organisms



Infectious:

J udgment• Pros

– Verrucous morphology

reflecting

pseudoepitheliomatous

hyperplasia

• Cons

– No clear exposure

– Chronic history

– No obvious underlying

immunosuppression









• Halogenoderma



Halogenoderma: Clinical

• Skin eruptions in response to exposure to

halides (bromide, iodide, fluoride)

• Acneiform papulonodular eruptions, pustular, vegetating plaques

• ?delayed hypersensitivity



Halogenoderma: Pathology

• Papillomatous epidermal hyperplasia

• Mixed inflammatory microabscesses with

ulceration



Halogenoderma:

J udgment

• Pros

– Morphology of

verrucous hyperplasia

could be consistent

• Cons

– No clear exposure

– Lacks acneiform or

pustular lesions

– Extensive distribution

of lesions atypical



Goals











• Variant of lupus erythematosus – Hypertrophic variant

– Lichen planus/lupus erythematosus overlap


• Halogenoderma• Cutaneous T-cell lymphoma



Cutaneous T-Cell Lymphomas:

WHO-EORTC Classification• Mycosis fungoides

• MF-variants – Pagetoid reticulosis

– Folliculotropic, syringotropic, granulomatous variants

• Subtype of MF – Granulomatous slack skin

• Sezary syndrome• CD30-positive lymphoproliferative disorders – Lymphomatoid papulosis

– Primary cutaneous anaplastic large cell lymphoma

• Subcutaneous panniculitis-like T-cell lymphoma

• Primary cutaneous peripheral T-cell lymphoma (PTL), unspecified

• Subtypes of PTL – Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)

– Cutaneous gamma/delta-positive T-cell lymphoma (provisional)

– Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

• Adult T-cell lymphoma

• Angioimmunoblastic T-cell lymphoma








• Sezary syndrome• CD30-positive lymphoproliferative disorders – Lymphomatoid papulosis









C



Cutaneous T-cell Lymphoma:

Clinical• Mycosis Fungoides

– Progression

• Patch

• Plaque• Tumor

• Erythroderma

– Sun-protected distribution

• CD30+ T-cell Lymphoproliferative Disorders – Lymphomatoid papulosis

– CD30+ anaplastic large cell lymphoma

M i F id



Mycosis Fungoides-

Background • History: Coined in 1806 by

Alibert for resemblance to

fungating tumors

• Epidemiology: Male:Female =2:1; Black > White; Median age

55 yo

• Incidence: 0.29/100,000/yr

• Etiology: ?HTLV-1; ?ionizingradiation; ?chronic antigen

stimulation (silicone breast

implants)

Cutaneous Lymphoma:



Cutaneous Lymphoma:

Mycosis Fungoides, Patch Stage-

Clinical

Cutaneous Lymphoma:



Cutaneous Lymphoma:

Mycosis Fungoides, Plaque Stage-

Clinical

Cutaneous Lymphoma:



Cutaneous Lymphoma:

Mycosis Fungoides, Tumor Stage-

Clinical

C t L h M i



Cutaneous Lymphoma, Mycosis

Fungoides: Pathology

• Epidermis

– Epidermotropism of atypical lymphocytes

• Pautrier’s microabscesses

• Haloed lymphocytes along dermal-epidermal junction

– Relative paucity of spongiosis

• Dermis – Papillary dermal sclerosis

– Lymphocytic atypia



Mycosis Fungoides: Pathology

M i F id



Mycosis Fungoides:

Immunophenotype

• CD3 • CD20

M i F id



Mycosis Fungoides:

Immunophenotype

• CD4 • CD7

C t T C ll L h








• Sezary syndrome

• CD30-positive lymphoproliferative disorders – Lymphomatoid papulosis









CD30+ P i C t



CD30+ Primary Cutaneous

Lymphoproliferative Disorders:

Clinical• Lymphomatoid papulosis

– Crops of red papulonodules, often localized – Remitting and recurring

• Primary cutaneous CD30+ T-cell

lymphoma – Larger, more persistent nodule

– Often ulcerated

CD30+ P i C t





Clinical

CD30+ Primar C taneo s

http://mail.google.com/mail/?realattid=f_etgdx49g&attid=0.1&disp=inline&view=att&th=10e5ddb95681d30a





Clinical




y


Pathology• Epidermis

– Variable spongiosis, acanthosis

– Epidermotropism not characteristic

• Dermis

– Heavy mixed infiltrate of atypical lymphocytes

– Types

• A• B

• C

Differential Diagnosis:Disseminated verrucous




papulonodules• Disseminated squamous cell carcinomas

– Multiple keratoacanthomas – Verrucous carcinomas





– Disseminated pagetoid reticulosis(Ketron-Goodman)



Pagetoid Reticulosis: Clinical

• History – Epidemiology

• Age: middle-aged to elderly

• Sex: M>F

– Course: acral hyperkeratotic plaques, slowly progressive

• Physical

– Morphology: verrucous, psoriasiform, hyperkeratotic patches, plaques, and nodules, usually on extremities

– Secondary Characteristics: hemorrhage and ulceration

– Distribution

• Localized: Woringer-Kolopp

• Disseminated: Ketron-Goodman



Pagetoid Reticulosis: Pathology

• Histology – Epidermal hyperplasia with hyperkeratosis

– Pattern• Lichenoid infiltrate

• Epidermotropism prominent, pagetoid and linear • Spongiosis variable

• Dyskeratosis variable

• Follicular, adnexal, and vascular involvement reported

– Cytomorphology• Medium/large pleomorphic T cells

• Hyperchromatic and cerebriform nuclei• Abundant vacuolated cytoplasm

• Dermal lymphocytic population normal




• Immunophenotype

– CD3+, CD4+, CD8- (majority)

– CD3+, CD4-, CD8+ (minority) – CD30+ (often)




Differential Diagnosis:Disseminated verrucous




papulonodules• Disseminated squamous cell carcinomas

– Multiple keratoacanthomas – Verrucous carcinomas





– Disseminated pagetoid reticulosis(Ketron-Goodman)

– Aggressive epidermotropic cytotoxic CD8+ cutaneous lymphoma



Goals

• To review the remarkably varied clinicaldifferential diagnosis for disseminated ulcerated,verrucous, plaques

• To use the clinical and reported pathologic data toarrive at a most likely diagnosis• To review the entity of primary cutaneous

aggressive, epidermotropic, cytotoxic CD8-positive lymphoma

• To try to account for the apparently evolvingmorphologyof the lesions

Aggressive Epidermotropic CD8+



Aggressive Epidermotropic CD8+

CTCL: Evolution of Concept

Histologic Patterns

Immunophenotypic

Characterization

Clinical Observations

Cutaneous T-cell Lymphoma with



Suppressor/Cytotoxic (CD8)

Phenotype• Agnarsson BA et al. J AAD 1990;22:569-77.

Nine patients.

• CD8+ cutaneous T cell lymphoma can be rapidly progressive or chronic.

• Distinction cannot be made by histology alone.

• Rapid progression was associated with CD2-,

CD7+ phenotype.• Chronicity was associated with CD2+, CD7-

phenotype.

Clinical and Pathological



Spectrum of CD8-positive

Cutaneous T-cell Lymphomas• Lu E et al. J Cutan Pathol 2002;29:465-472.

• Four groups:

– Precedent history of rash progression similar to CD4+ MF (7)

– Long-standing localized plaques similar to PR (3)

– Erythroderma and peripheral blood involvement similar to SS (2)

– Cutaneous nodules (6)

• Histology: epidermotropism, prominent periadnexal

infiltration• Conclusion: Approximately half of CD8+ CTCL clinically

and histologically resemble CD4+ MF/SS

Primary Cutaneous Aggressive



Epidermotropic CD8+ Cytotoxic

T-cell Lymphoma: Clinical

• History

– Epidemiology

• Age: middle-aged to elderly

• Sex: M>F

– Symptoms: rapidly progressive ulcerated plaques

without antecedent patch-plaque evolution

– Associated Findings:

• Systemic involvement, including oral cavity, testis, lung, CNS,

soft tissues

• Lymph nodes spared





T-cell Lymphoma: Clinical

• Physical

– Morphology: patches, plaques, and nodules – Secondary Characteristics: hemorrhage and

ulceration

– Distribution: generalized

– Other Findings: findings referable to systemic

involvement (oral cavity, lung, CNS, etc)





T-cell Lymphoma: Pathology

• Histology

– Pattern

• Lichenoid infiltrate

• Epidermotropism prominent, pagetoid and linear

• Spongiosis variable

• Dyskeratosis variable

• Follicular, adnexal, and vascular involvement reported

– Cytomorphology

• Medium/large pleomorphic T cells





T-cell Lymphoma: Pathology

• Immunohistochemistry

– CD3+, CD4-, CD8+, CD45RA+, CD45RO- – CD2-/+, CD5-/+, CD7+/-

– TIA-1+, bcl-2+, MIB-1+

– CD56+/- • Molecular Genetics

– TCR-gamma genes rearranged





T-cell Lymphoma: Management

• Course

– Fatal outcome in most

– Mean survival 32 months

• Treatment

– Chemotherapy (purine analogs)

– Radiotherapy

– Allogeneic bone marrow transplant

– Avoid therapy (e.g. retinoids, IFN-alpha) thatenhances Th1-like cytokine profile

Cutaneous T-cell Lymphoma:



Cutaneous T cell Lymphoma:

Specific Classification

• Pagetoid Reticulosis

– Hyperkeratotic, verrucous

plaques on hands and feet

– Woringer and Kolopp

(localized) vs. Ketron-

Goodman (disseminated)

– Prominent pagetoid spread

• Primary CutaneousAggressiveEpidermotropic CD8+ T-

cell Lymphoma – Eruptive papulonodules

with chronic patches and

psoriasiform plaques

– Papulonodules: prominent

acanthosis or even pseudoepitheliomatous

hyperplasia

Resolution: Disseminated PR versus



versus

Aggressive Epidermotropic CD8+CTCL

• “Generalized cases [of pagetoid reticulosis]

would currently likely be classified asaggressive epidermotropic CD8+ CTCL,

cutaneous gamma/delta-positive T-cell

lymphoma, or tumor-stage MF.” [WillemzeR, et al. Blood 2005;105:3768-3785.]



Perspective

Disseminated Hyperkeratotic Papulonodular Lesions


Epidermotropic CD8+ CytotoxicT-cell Lymphoma

Disseminated Pagetoid Reticulosis



Goals

• To review the remarkably varied clinicaldifferential diagnosis for disseminated ulcerated,verrucous, plaques

• To use the clinical and reported pathologic data toarrive at a most likely diagnosis• To review the entity of primary cutaneous

aggressive, epidermotropic, cytotoxic CD8-positive lymphoma

• To try to account for the apparently evolvingmorphologyof the lesions

C i i S



Clinical Summary

• 44 year old Caucasian woman – 2.3-year history of generalized hyperkeratotic verrucous

papulonodules – admitted for fever and purulent drainagefrom ulcerated annular

plaquesand tumorsfor the past 2 months

– following an episode of presumed levofloxacin cutaneoushypersensitivity

– with work-up to date notable for skin pathology interpreted assquamous cell carcinomaand laboratory tests showing a positiveANA, positive anti-U1 snRNP, anemia, leukocytosis with a leftshift, and thrombocytosis

– and minimal improvement to treatment with topical and systemicsteroids, topical tacrolimus, systemic hydroxychloroquine, PUVA,oral antibiotics, isotretinoin, and mycophenolate

Synthesis:



Synthesis:

Two scenarios

• Separate processes

– Generalized keratoacanthomas/squamous cellcarcinomas as paraneoplastic phenomenon

– Drug rash

– Cutaneous T-cell lymphoma

• Unified process

– Possibly immunosuppression-associatedmanifestations of evolving lymphomatous

process

Scenario A



Exacerbation of



T-cell Lymphoma

with Retinoid Use

Fully Evolved



T-cell Lymphoma

Hyperkeratotic Papulonodules

As Early/SmolderingManifestation of Aggressive


T-cell Lymphoma

Scenario B



Exacerbation of



T-cell Lymphoma

with Retinoid Use

Fully Evolved



T-cell Lymphoma

Multiple

Keratoacanthomas

As

ParaneoplasticPhenomenon

Primary Cutaneous AggressiveEpidermotropic CD8+ T-cell



Epidermotropic CD8 T cell

Lymphoma:

J udgment• Pros

– Hyperkeratotic,

verrucous lesionscompatible with

reported morphology

– Ulcerated lesions

classic for morphology – Rapid downturn of

events compatible with

aggressive course

• Cons

– Somewhat uncertain

significance of evolving morphology



Diagnosis:Primary Cutaneous Aggressive

Epidermotropic CD8+ CytotoxicT-cell Lymphoma



Pathology

Alison Z. Young, M.D., Ph.D.



Skin Biopsy: Left elbow











CD3 CD20



CD4 CD8

Initial Diagnostic Consideration



Initial Diagnostic Consideration

• Mycosis Fungoides

• Note: The degree of atypia of the nuclei is

unusual.



Skin Biopsy: Right neck









Skin Biopsy: Right Abdomen









CD20 CD3



CD4



CD4



CD8



CD8



CD7

CD2

CD30CD25



Perforin



BF-1

Immunophenotype



Immunophenotype

• CD20-• CD3+

• CD8+

• CD4+ (scattered)

• CD7+

• CD2-

• CD30-

• CD25+

• Perforin+

• BF-1+

Molecular Diagnostics



Molecular Diagnostics

• Clonal rearrangement to V9 and V10 (TCR

gamma chain)

Final Pathologic Diagnosis



Final Pathologic Diagnosis

• Aggressive epidermotropic cytotoxic

CD8+ cutaneous T-cell lymphoma



Skin Biopsy: Right Thigh







Diagnosis



Diagnosis

• Atypical Squamous Proliferation suggestive

of Squamous Cell Carcinoma

• In retrospect: – No morphologic evidence of lymphoma

– No tissue available for immunophenotyping or

genetic studies

– Pseudoepitheliomatous hyperplasia as a

paraneoplastic phenomenon cannot be excluded



Skin Biopsy: Right Abdomen







Diagnosis



Diagnosis

• Acute Spongiotic Dermatitis with

Eosinophilia and Focal Interface Changes

• In retrospect – Atypical cells are present that likely represent

involvement by the patient’s lymphoma.

Epidermotropic CD8+ CTCL

• Aggressive clinical course (median survival 32



Aggressive clinical course (median survival 32months)

• Eruptive papules, plaques & tumors with centralulceration & necrosis

• Metastatic spread to spleen, lungs, liver, CNS, oralcavity & rarely to lymph nodes

• Band-like infiltrate of medium-sized pleomorphic Tcells with a CD3+, CD4-, CD8+ phenotype

• Prominent epidermotropism into an acanthoticepidermis with spongiosis and blistering in all stages

• Cases with fatal outcome are CD2- & CD7+• Rx: multi-agent chemotherapy, bone marrow

transplant

CD8+ CTCL vs Transformed MF



CD8+ CTCL vs PagetoidReticulosis



CD8+ CTCL vs CD30- CutaneousLarge T-cell Lymphoma



PEH in association with PrimaryCutaneous ALCL



AE1/AE3

CD30



Final Diagnosis

Aggressive CD8+ Epidermotropic

Cytotoxic CTCL with

Pseudoepitheliomatous Hyperplasia



Clinical Course

Corey Cutler, MD MPH FRCP(C)

Department of Hematologic Oncology andStem Cell Transplantation

Dana-Farber Cancer Institute

Clinical Course



• Received 8 courses of dose-intense

Cyclophosphamide, Adriamycin, Vincristine and

Prednisone (CHOP-14 x 8)

• Attains 1st Clinical Complete Remission

• Early Relapse – Responds to CHOP again

• Signs of early cutaneous recurrence within weeks

Clinical Course



• Undergoes Fully Ablative Allogeneic Stem

Cell Transplantation from a Matched,

Unrelated Donor

– Cyclophosphamide (1800 mg/m2 x 2)

– Total Body Irradiation (14 Gy in 7 fractions)

• Complete disappearance of all skin lesions

after near total desquamation

Clinical Course



• Day +24: New diffuse erythema – clinicallyand histologically consistent with acuteGraft-vs.-Host Disease (Stage 3 Skin,

Overall Grade IIC)• Responds to prednisone

• During prednisone taper (~day +150), new

plaque-like skin lesions noted over torso,limbs and scalp

Clinical Course



• Biopsy: Slight spongiosis with parakeratosis

and intracorneal pustules consistent with

early evolving psoriasis

• Responsive to topical high-potency

corticosteroid therapy

• Alive, with skin lesions of unknown

significance, day +165

Transplantation for CTCL



p

• Rarely performed;

• Heterogeneous literature – case reports,

case series(Molina et al , J Clin Onc 2005)

• Varying outcomes

• DFCI experience, n=3; All alive and

disease-free between 165-300 days; Allwith cutaneous GVHD



References: Disseminated Squamous

Cell Carcinomas



Cell Carcinomas

• Cruickshank AH, McConnell EM, Miller DG. Malignancy in scars,chronic ulcers, and sinuses. J Clin Pathol 1963;16:573-580.

• Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skincancer in 5356 patients following organ transplantation. Br J Dermatol2000;143:513-519.

• Jayaraman M, Janaki VR, Yesudian P. Squamous cell carcinomaarising from hypertrophic lichen planus. Int J Dermatol 1995;34:70-71.

• Castano E, Lopez-Rios F, Alvare-Fernandez JG, et al. Verrucouscarcinoma in association with hypertrophic lichen planus. Clin Exp

Dermatol 1997;22P23-25.• Badell A, Marcoval J, Gallego I, et al. Keratoacanthoma arising in

hypertrophic lichen planus. Br J Dermatol 2000;142:380-382.

References: Lupus Erythematosus



• Santa Cruz DJ, Uitto J, Eisen AZ, Prioleau PG. Verrucous lupus erythematosus: Ultrastructuralstudies on a distinct variant of chronic discoid lupus erythematosus. J Am Acad Dermatol1983;9:82-90.

• Rubenstein DJ, Huntley AC. Keratotic lupus erythematosus: treatment with isotretinoin. J AmAcad Dermatol 1986;14:910-914.

• Van der Horst JC, Cirkel PKS, Nieboer C. Mixed lichen planus-lupus erythematosus disease: adistinct entity? Clinical, histopathological and immunopathological studies in six patients. Clin ExpDermatol 1983;8:631-640.

• Inaloz HS, Chowdhury MMU, Motley RJ. Lupus erythematosus/lichen planus overlap syndromewith scarring alopecia. J Eur Acad Dermatol Venereol 2001;15:171-174.

• Friss AB, Cohen PR, Bruce S, Duvic M. Chronic cutaneous lupus erythematosus mimickingmycosis fungoides. J Am Acad Dermatol 1995;33:891-895.

• Plotnick H, Burnham TK. Lichen planus and coexisting lupus erythematosus versus lichen planus-like lupus erythematosus. J Am Acad Dermatol 1986;14:931-938.

• Uitto J, Santa-Cruz DJ, Eisen AZ, Leone P. Verrucous lesions in patients with discoid lupus.Clinical, histopathological and immunofluorescence studies. Br J Dermatol 1978;98:507-520.

• Perniciaro C, Randle HW, Perry HO. Hypertrophic discoid lupus erythematosus resemblingsquamous cell carcinoma. Dermatol Surg 1995;21:255-257.

References: Infectious



• Quimby SR, Connolly SM, Winkelmann

RK, Smilack JD. Clinicopathologic

spectrum of specific cutaneous lesions of

disseminated coccidiodomycosis. J Am

Acad Dermatol 1992;26:79-82.

• Hobbs ER, Hempstead RW. Cutaneous

coccidiodomycosis simulating lepromatous

leprosy. Int J Dermatol 1984;23:334-336.

References: Cutaneous T-cell

Lymphoma



Lymphoma• Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005:

histological and molecular aspects. J Cutan Pathol 2005;32:647-674.

• LeBoit PE. Variants of mycosis fungoides and related cutaneous T-cell lymphomas. Sem DiagPathol 1991;8:73-81.

• Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T cell lymphoma with suppressor/cytotoxic(CD8) phenotypes: Identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol1990;22:569-577.

• Price NM, Fuks ZY, Hoffman TE. Hyperkeratotic and verrucous features of mycosis fungoides.

Arch Dermatol 1977;113:57-60.• Tyring SK, Jones CS, Lee PC, et al. Development of verrucous plaques and gross hematuria in

advanced cutaneous T-cell lymphoma. Arch Dermatol 1988;124:655-656.

• Caputo R, Monti M, Berti E, et al. A verrucoid epidermotropic OKT8-positive lymphoma. Am JDermatopathol 1990;5:159-164.

• Courville P, Wechsler J, Thomine E, et al. Pseudoepitheliomatous hyperplasia in cutaneous T-celllymphoma. A clinical, histopathological and immunohistochemical study with particular interest inepithelial growth factor expression. Br J Dermatol 1999;140:421-426.

• Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas:Report of the EORTC cutaneous lymphoma task force workshop Cancer 2003;97:610 627

Documents

Case 38, 2007-Gen Painful Ulcersted Lesions