Case 38, 2007-Gen Painful Ulcersted Lesions

Clinicopathologic Conference HMS Dermatopathology Course
October 20, 2006

Vincent Liu, M.D.
Dermatology and Dematopathology University of Iowa School of Medicine Iowa City, IA
Alison Z. Young, M.D., Ph.D.

Dermatology Virginia Mason Medical Center Seattle, WA
HPI #1/11: Original Lesions, 2.3 years prior to admission

Erosions on scalp developed soon after beginning sumatriptin for headaches Subsequent diffuse scaly erythematous papules and plaques over the rest of the body, resistant to topical steroid and cephalexin
HPI #2/11: Outside Dermatology Evaluation

Scarring alopecia and multiple hyperkeratotic erythematous plaques on the trunk and arms Pathology of hyperkeratotic plaque: hypertrophic lichenoid dermatitis with eosinophilia Bloodwork: leukocytosis (13.6K) with negative ANA Topical and systemic corticosteroids and hydroxychloroquine-> some improvement Three months later, topical tacrolimus and cephalexin course Psoralen-UVA photochemotherapy 23 months prior to admission, erythematous lesions arose on face and left lower eyelid
HPI #3/11: Initial Presentation to MGH Clinic (14 months PTA)

Tender 3-6 cm plaques and nodules over face, trunk, and extremities, some eroded, appearing lichenoid to hypertrophic to verrucous Bloodwork: rheumatologic serologies negative Treatment: topical tacrolimus and clobetasol cream
HPI #4/11: Squamous Cell Carcinoma-like Lesions

Biopsy of verrucous lesion on right thigh: welldifferentiated invasive squamous cell carcinoma Left lower leg lesion removed by Mohs surgery three weeks later, revealing well-differentiated invasive squamous cell carcinoma Treatment: isotretinoin (20 mg daily) On follow-up (10 months PTA) boggy, erythematous, irregular thin plaque in the left inframammary area and an oozing, crusted lesion over the left lateral deltoid seen, treated with topical 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 and erythema, ectropion, lagophthalmos, and exposure keratopathy, 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 cell carcinoma New England Dermatological Society discussion: eruptive keratoacanthoma versus squamous cell carcinoma versus verrucous carcinoma versus hypertrophic lichen planus versus lupus erythematosus Previous biopsy specimen testing: negative for 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 lesions with necrotic black central ulcerations developed Readmission to hospital
HPI #8/11: Evaluation on Admission

Morphology: Painful erythematous target and reniform lesions with 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 on the legs with minimal involvement of the scalp, palms, and soles Associated finding: Left periorbital edema and erythema
HPI #9/11: Hospitalization #2 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 Levofloxacin begun Prednisone taper Morphine pain control
HPI #10/11: Third rash (1 month PTA)

Ten days later, new blanching erythematous lesions between target lesions on trunk and extremities: diagnosed as levofloxacin hypersensitivity Treatment: discontinued levofloxacin; started topical mupirocin Response:
Some of the ulcerated lesions flattened and crusted over, but most persisted Pain required narcotic analgesia Hair & nail testing negative for arsenic
HPI #11/11: Hospitalization #3

Three weeks after discharge, fever (38 degrees F), purulent drainage from lesions on the right foot and left axilla
Culture: S. aureus, P. aeruginosa Treatment: topical mupirocin
Readmitted with persistent fever
Past Medical History

Eczema at age 24, generalized but sparing face, with winter exacerbation, treated with topical steroids and tacrolimus Migraine headaches, 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 Fathers 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), bp WNL, resp WNL Skin:
Generalized, confluent annular ulcerated plaques, covering >60-70% BSA Multiple 0.5-cm hyperkeratotic papules, predominantly on legs Erosions and deep ulcerations on right neck, right breast, right heel with green discharge Left periorbital swelling and erythema 2+ edema bilateral 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 (1:640 speckled); positive anti-U1 sn-RNP T-cell subsets: normal CD4:CD8 ratio (4 mos PTA) SPEP: abnormal pattern- v. low concn bands in gamma region, 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 drainage from ulcerated annular plaques and tumors for 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 carcinoma and laboratory tests showing a positive ANA, 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 patients cutaneous manifestations reflect the same process (Occams razor)? If there are multiple processes, is there causality in 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 patients history of eczema? What is the role, if any, of medication-induced immunosuppression in the pathogenesis?
Goals
To review the remarkably varied clinical differential diagnosis for 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 apparently evolving morphology of the lesions
Goals
Differential Diagnosis: Disseminated verrucous papulonodules

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Disseminated squamous cell carcinomas
Disseminated Squamous Cell Carcinomas: Clinical Settings

Sun-exposed Scars (Marjolins)
Trauma Burns Frostbite Vaccination scars Pyoderma gangrenosum Dystrophic epidermolysis bullosa Hailey-Hailey disease Porokeratosis Discoid lupus erythematosus Lichen planus
Underlying conditions
Immunosuppression- organ transplant recipients
Squamous Cell Carcinomas: Clinical
Squamous Cell Carcinomas: 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
Squamous Cell Carcinomas: Pathology

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

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 (epithelioma cuniculatum)
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 Chromomycosis Sporotrichosis Aspergillosis Pyoderma Actinomycosis Chronic verrucous lesions in immunocompromised patients with HSV/VZV
Neoplastic
Spitz nevi Malignant melanoma Granular cell tumor Cutaneous T-cell lymphoma
Infections
Dermal inflammatory processes

Halogenodermas Chondrodermatitis nodularis helicis

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 giant cells Endospores within spherules (sporangia)
Systemic Mycoses: Blastomycosis

Clinical
Three forms:
Pulmonary Disseminated Primary cutaneous
North America, Africa, India Crusted verrucous nodule or 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 giant cells
Systemic Mycoses: Histoplasmosis

Clinical
America, Africa, Asia Dimorphic soil fungus Lung is primary focus Immunosuppression predisposes to dissemination, with skin involved in 5% 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 surrounding clear 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 with asteroid bodies


Mycoses Mycobacterial infection
Mycobacterial Infection: Clinical
Multiple Squamous Cell Carcinomas/Keratoacanthomas/ Verrucous Carcinomas: Judgment

Pros
Pathology suggestive Multiple lesions documented
Cons
No clear underlying association in this case No classic (GI/GU) malignancy No significant response to systemic retinoids Generalized distribution Negative HPV testing



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 lymphocytic inflammation Mucin deposition Transepidermal elimination of elastotic material
Lupus Erythematosus: Pathology
Lupus Erythematosus, Hypertrophic Variant: Pathology


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 Planus/Lupus Erythematosus Overlap: Pathology

Verruciform papillomatous hyperplasia with brisk lichenoid lymphocytic inflammation
Lupus Erythematosus Variant: Judgment

Pros
Positive serologies (ANA, anti-U1 snRNP) Reports of squamous cell carcinoma development in hypertrophic lupus erythematosus
Cons
Lacks other ARA criteria for lupus erythematosus Generalized distribution and density of lesions unusual


Infectious: Categories
Mycoses
Systemic
Coccidiodomycosis Blastomycosis Histoplasmosis Cryptococcosis Paracoccidiodomycosis (in AIDS)
Dematiaceous
Chromomycosis Sporotrichosis
Mycobacterial
Lepromatous leprosy Atypical mycobacterial
Treponemal
Yaws Bejel
Leishmanial
Lupus Erythematosus, Hypertrophic Variant: Clinical

Discoid lupus erythematosus lesions with verrucous, hypertrophic morphology Disseminated lesions
cutaneous LE systemic LE
Photodistribution (face and arms) More recalcitrant to therapy
Lupus Erythematosus: Clinical


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 with daughter 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, and granulocytes No endothelial swelling Resemble condylomata lata Spirochetes between keratinocytes
Treponemal Infection, Yaws: Pathology

Papillomatous epidermal hyperplasia, spongiosis Intraepidermal microabscesses Treponemes in epidermis


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: Judgment
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: Judgment
Pros
Morphology of verrucous hyperplasia could be consistent
Cons
No clear exposure Lacks acneiform or pustular lesions Extensive distribution of lesions atypical
Goals


Halogenoderma Cutaneous T-cell lymphoma
Cutaneous T-Cell Lymphomas: WHO-EORTC Classification

Mycosis fungoides MF-variants
Pagetoid reticulosis Folliculotropic, syringotropic, granulomatous variants Granulomatous slack skin
Subtype of MF 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


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
Mycosis FungoidesBackground
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; ?ionizing radiation; ?chronic antigen stimulation (silicone breast implants)
Cutaneous Lymphoma: Mycosis Fungoides, Patch StageClinical
Cutaneous Lymphoma: Mycosis Fungoides, Plaque StageClinical
Cutaneous Lymphoma: Mycosis Fungoides, Tumor StageClinical
Cutaneous Lymphoma, Mycosis Fungoides: Pathology

Epidermis
Epidermotropism of atypical lymphocytes
Pautriers microabscesses Haloed lymphocytes along dermal-epidermal junction
Relative paucity of spongiosis
Dermis
Papillary dermal sclerosis Lymphocytic atypia
Mycosis Fungoides: Pathology
Mycosis Fungoides: Immunophenotype

CD3 CD20
Mycosis Fungoides: Immunophenotype

CD4 CD7


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
Epidermis
CD30+ Primary Cutaneous Lymphoproliferative Disorders: Pathology

Variable spongiosis, acanthosis Epidermotropism not characteristic
Dermis
Heavy mixed infiltrate of atypical lymphocytes Types
A B C



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 Medium/large pleomorphic T cells Hyperchromatic and cerebriform nuclei Abundant vacuolated cytoplasm Dermal lymphocytic population normal
Cytomorphology

Immunophenotype
CD3+, CD4+, CD8- (majority) CD3+, CD4-, CD8+ (minority) CD30+ (often)



Disseminated pagetoid reticulosis (Ketron-Goodman) Aggressive epidermotropic cytotoxic CD8+ cutaneous lymphoma
Goals
To review the remarkably varied clinical differential diagnosis for disseminated ulcerated, verrucous, plaques To use the clinical and reported pathologic data to arrive at a most likely diagnosis To review the entity of primary cutaneous aggressive, epidermotropic, cytotoxic CD8positive lymphoma To try to account for the apparently evolving morphology of the lesions
Aggressive Epidermotropic CD8+ CTCL: Evolution of Concept
Clinical Observations
Histologic Patterns
Immunophenotypic Characterization
Cutaneous T-cell Lymphoma with Suppressor/Cytotoxic (CD8) Phenotype

Agnarsson BA et al. JAAD 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+, CD7phenotype.
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
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic 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)
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic 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
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma: Pathology

Immunohistochemistry
CD3+, CD4-, CD8+, CD45RA+, CD45ROCD2-/+, CD5-/+, CD7+/TIA-1+, bcl-2+, MIB-1+ CD56+/-
Molecular Genetics
TCR-gamma genes rearranged
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic 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) that enhances Th1-like cytokine profile
Cutaneous T-cell Lymphoma: Specific Classification

Pagetoid Reticulosis
Hyperkeratotic, verrucous plaques on hands and feet Woringer and Kolopp (localized) vs. KetronGoodman (disseminated) Prominent pagetoid spread
Primary Cutaneous Aggressive Epidermotropic CD8+ Tcell Lymphoma

Eruptive papulonodules with chronic patches and psoriasiform plaques Papulonodules: prominent acanthosis or even pseudoepitheliomatous hyperplasia
Resolution: Disseminated PR versus Aggressive Epidermotropic CD8+ CTCL

Generalized cases [of pagetoid reticulosis] would currently likely be classified as aggressive epidermotropic CD8+ CTCL, cutaneous gamma/delta-positive T-cell lymphoma, or tumor-stage MF. [Willemze R, et al. Blood 2005;105:3768-3785.]
Perspective
Disseminated Hyperkeratotic Papulonodular Lesions
Disseminated Pagetoid Reticulosis
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma
Goals
To review the remarkably varied clinical differential diagnosis for disseminated ulcerated, verrucous, plaques To use the clinical and reported pathologic data to arrive at a most likely diagnosis To review the entity of primary cutaneous aggressive, epidermotropic, cytotoxic CD8positive lymphoma To try to account for the apparently evolving morphology of the lesions
Clinical Summary
44 year old Caucasian woman
2.3-year history of generalized hyperkeratotic verrucous papulonodules admitted for fever and purulent drainage from ulcerated annular plaques and tumors for 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 carcinoma and laboratory tests showing a positive ANA, 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
Synthesis: Two scenarios

Separate processes
Generalized keratoacanthomas/squamous cell carcinomas as paraneoplastic phenomenon Drug rash Cutaneous T-cell lymphoma
Unified process
Possibly immunosuppression-associated manifestations of evolving lymphomatous process
Scenario A
Hyperkeratotic Papulonodules As Early/Smoldering Manifestation of Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma Exacerbation of Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma with Retinoid Use
Fully Evolved Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma
Scenario B
Multiple Keratoacanthomas As Paraneoplastic Phenomenon Exacerbation of Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma with Retinoid Use
Fully Evolved Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma
Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma: Judgment

Pros
Hyperkeratotic, verrucous lesions compatible 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+ Cytotoxic T-cell Lymphoma
Pathology
Alison Z. Young, M.D., Ph.D.
Skin Biopsy: Left elbow
CD3
CD20
CD4
CD8
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
CD2 CD7
CD30
CD25
Perforin
BF-1
Immunophenotype
CD20CD3+ CD8+ CD4+ (scattered) CD7+ CD2CD30CD25+ Perforin+ BF-1+
Molecular Diagnostics
Clonal rearrangement to V9 and V10 (TCR gamma chain)
Final Pathologic Diagnosis

Aggressive epidermotropic cytotoxic CD8+ cutaneous T-cell lymphoma
Skin Biopsy: Right Thigh
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
Acute Spongiotic Dermatitis with Eosinophilia and Focal Interface Changes In retrospect
Atypical cells are present that likely represent involvement by the patients lymphoma.
Epidermotropic CD8+ CTCL

Aggressive clinical course (median survival 32 months) Eruptive papules, plaques & tumors with central ulceration & necrosis Metastatic spread to spleen, lungs, liver, CNS, oral cavity & rarely to lymph nodes Band-like infiltrate of medium-sized pleomorphic T cells with a CD3+, CD4-, CD8+ phenotype Prominent epidermotropism into an acanthotic epidermis 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 Pagetoid Reticulosis
CD8+ CTCL vs CD30- Cutaneous Large T-cell Lymphoma
PEH in association with Primary Cutaneous 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 and Stem 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 clinically and histologically consistent with acute Graft-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

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; All with cutaneous GVHD
References: Disseminated Squamous 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 skin cancer in 5356 patients following organ transplantation. Br J Dermatol 2000;143:513-519. Jayaraman M, Janaki VR, Yesudian P. Squamous cell carcinoma arising from hypertrophic lichen planus. Int J Dermatol 1995;34:7071. Castano E, Lopez-Rios F, Alvare-Fernandez JG, et al. Verrucous carcinoma 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: Ultrastructural studies on a distinct variant of chronic discoid lupus erythematosus. J Am Acad Dermatol 1983;9:82-90. Rubenstein DJ, Huntley AC. Keratotic lupus erythematosus: treatment with isotretinoin. J Am Acad Dermatol 1986;14:910-914. Van der Horst JC, Cirkel PKS, Nieboer C. Mixed lichen planus-lupus erythematosus disease: a distinct entity? Clinical, histopathological and immunopathological studies in six patients. Clin Exp Dermatol 1983;8:631-640. Inaloz HS, Chowdhury MMU, Motley RJ. Lupus erythematosus/lichen planus overlap syndrome with scarring alopecia. J Eur Acad Dermatol Venereol 2001;15:171-174. Friss AB, Cohen PR, Bruce S, Duvic M. Chronic cutaneous lupus erythematosus mimicking mycosis fungoides. J Am Acad Dermatol 1995;33:891-895. Plotnick H, Burnham TK. Lichen planus and coexisting lupus erythematosus versus lichen planuslike 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 resembling squamous 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

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 Diag Pathol 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 Dermatol 1990;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 J Dermatopathol 1990;5:159-164. Courville P, Wechsler J, Thomine E, et al. Pseudoepitheliomatous hyperplasia in cutaneous T-cell lymphoma. A clinical, histopathological and immunohistochemical study with particular interest in epithelial 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.

Case 38, 2007-Gen Painful Ulcersted Lesions

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Case 38, 2007-Gen Painful Ulcersted Lesions

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Clinicopathologic Conference HMS Dermatopathology Course

October 20, 2006

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

HPI #1/11: Original Lesions, 2.3 years prior to admission

HPI #2/11: Outside Dermatology Evaluation

HPI #3/11: Initial Presentation to MGH Clinic (14 months PTA)

HPI #4/11: Squamous Cell Carcinoma-like Lesions

HPI #5/11: Hospital Admission #1 (8 months PTA)

HPI #6/11: Evolution of Lesions

HPI #7/11: Hospitalization #2 (2-3 months PTA)

HPI #8/11: Evaluation on Admission

HPI #9/11: Hospitalization #2 Work-up

HPI #10/11: Third rash (1 month PTA)

HPI #11/11: Hospitalization #3

Readmitted with persistent fever

Past Medical History

Allergies and Medications

Questions: Challenge to Differential Diagnosis

Differential Diagnosis: Disseminated verrucous papulonodules

Differential Diagnosis: Disseminated verrucous papulonodules

Disseminated Squamous Cell Carcinomas: Clinical Settings

Immunosuppression- organ transplant recipients

Squamous Cell Carcinomas: Clinical

Squamous Cell Carcinomas: Clinical

Disseminated Squamous Cell Carcinomas: Pathology

Squamous Cell Carcinomas: Pathology

Disseminated squamous cell carcinomas

Differential Diagnosis: Disseminated verrucous papulonodules

Multiple Keratoacanthomas: Clinical

Multiple Keratoacanthomas as Paraneoplastic Phenomenon? Muir-Torre Syndrome

At least one visceral malignancy

Other cutaneous neoplasms

MSH2 gene mutation

Disseminated squamous cell carcinomas

Differential Diagnosis: Disseminated verrucous papulonodules

Verrucous Carcinomas: Clinical

Verrucous Carcinoma: Clinical

Verrucous Carcinomas: Pathology

Verrucous Carcinoma: Pathology

Pseudoepitheliomatous Hyperplasia: Pathology

Pseudoepitheliomatous Hyperplasia: Pathologic Differential Diagnosis

Dermal inflammatory processes

Disseminated squamous cell carcinomas

Differential Diagnosis: Disseminated verrucous papulonodules

Variant of lupus erythematosus

Dematiaceous Fungal Infections

Systemic Mycoses: Coccidiodomycosis

Systemic Mycoses: Blastomycosis

Systemic Mycoses: Histoplasmosis

Dematiaceous Mycoses: Sporotrichosis

Round or oval (4-6 micron) organisms uncommon with asteroid bodies

Disseminated squamous cell carcinomas

Differential Diagnosis: Disseminated verrucous papulonodules

Variant of lupus erythematosus

Mycobacterial Infection: Clinical

Multiple Squamous Cell Carcinomas/Keratoacanthomas/ Verrucous Carcinomas: Judgment

Disseminated squamous cell carcinomas

Differential Diagnosis: Disseminated verrucous papulonodules

Variant of lupus erythematosus

Disseminated squamous cell carcinomas

Differential Diagnosis: Disseminated verrucous papulonodules

Variant of lupus erythematosus

Lupus Erythematosus, Hypertrophic Variant: Pathology

Lupus Erythematosus: Pathology