[考生加油] Dermatological Recall: Chapter 32 Lichen Planus Part 1

扁平苔蘚(lichen planus)聽起來是很普通的疾病，但在皮膚科卻是成因相當複雜，且難以治療的燙手山芋(剛好也是紫色的)。長在頭皮與指甲的病灶如果太晚治療，甚至會造成頭髮與指甲不可逆的消失。儘管扁平苔癬在臨床上相對少見，遇到的時候趕快診斷並給予正確治療才最重要的事。

Chapter 32 :: Lichen Planus Part 1

:: Aaron R. Mangold & Mark R. Pittelkow

鄭煜彬(20200329)

INTRODUCTION
What is the meaning of lichen planus(LP)?	Flat(planus) tree moss(lichen)
What is the involved tissue of LP?	Any ectodermal-derived tissue
What is the classification of LP?	Papulosquamous lesion (however, it just has scant scales, not really “squamous”)
What is the four Ps of LP?	(1) purple, (2) polygonal, (3) pruritic, & (4) papules
What is the histological feature of LP?	A brisk lymphocytic interface reaction (lichenoid infiltration)
PATHOGENESIS
What contributing factors may cause LP?	Infectious, immune, metabolic, and genetic causes
What is the main responder of LP?	Cell–mediated immunity(T cells). Immunoglobulins (humoral immunity) is only secondary response.
What is the constitution of T cells in LP? (Th or Tc?)	Dermis: CD4+ T-helper (CD4-Th) Near basal keratinocytes: CD8+T-cytotoxic (CD8-Tc)
What is the 4 stages of LP?	antigen recognition, lymphocyte activation, keratinocyte apoptosis, resolution.
What is the pathogenesis of LP ?	Some antigen→Langerhans cell→↑MHC class II receptors→↑CD4-Th (antigen recognition of HLA-DR(+) keratinocyte)→release inflammatory cytokines (IFN-γ)→CD8-Tc oligoclonal expansion
What is the antigen of typical LP?	Unknown antigen
What is the antigen of lichenoid GVHD?	Alloantigens from the graft.
What is the antigen of oral LP?	MHC class I on keratinocytes (an autoreactive peptide or an exogenous antigen?)
What are the exogenous antigen of LP?	1.          Inorganic mercury (dental amalgam), gold (act as haptens) 2.          Syphilis, HSV 2, HIV, amebiasis, chronic bladder infections, HCV, Helicobacter pylori, or HPV.
What are the cause of TNF- α associated lichenoid tissue reactions(LTRs)?	TNF-α inhibitors (dysregulated cytokine) → upregulation of type I IFN)
What is the major cytokine in LP?	IFN-γ (↑migration of lymphocytes to DEJ)
How does IFN-γ work in LP?	↑inflammatory chemokines CXCL-9, 10, & 11→activate CXCR-3 on CD4-Th
Why does peroxisome-proliferator-activated receptor γ (PPARγ) stop scarring alopecia in LPP?	It inhibits CXCL-10 & 11
What is the mechanism of keratinocyte apoptosis in LP?	CD8-Tc cells→granzyme B release, TNF-α–TNF-α R1 receptor interaction, & Fas–Fas-L interaction
What is the mechanism of disruption of the basement membrane in LP?	TNF-α→↑matrix metalloproteinase-9 (MMP-9), especially in ulcerative lesions
What is the mechanism of the resolution of LP?	1.          T-regulatory cells→↓Tc 2.          Fas-L, granzyme B, & perforin on the keratinocytes: apoptosis of Tc
GENETIC AND EPIGENETIC REGULATION
What are the sites of gene polymorphisms related to LP?	HLA, immune signaling molecules & receptors (IFN-γ, TNF-α, TNF-α R2, IL-4, IL-6, IL-18, NF-κB), PGE2, oxidative stress, transglutaminase, thyroid hormone, & prothrombin.
What are miRNAs related to the epigenetic regulation of LP?	micro-RNA (miRNA)-146a & -155
What are the most specific marker of LP?	CXCR-3 ligand & CXCL-9,
EPIDEMIOLOGY
How much is the prevalence of LP?	1% (0.1-4%), but not exact.
What is the age of most LP?	30-60 y/o (2/3 of all cases)
What is the peak onset of LP?	>55 y/o (elderly, earlier in women)
How much is the prevalence of childhood LP?	1-5%, 20% in Pacific Indians. no sexual predilection
What is the peak onset of childhood LP?	Between 8 & 12 years of age
What is the features of familial LP?	Family history(廢話), early onset, widespread & erosive/ulcerative disease, mucosal involvement, & frequent relapses.
What is the HLA tendency in familial & nonfamilial LP?	Familial: HLA-B27, Aw19, -B18, & -Cw8 Nonfamilial: HLA-A3, -A5, -A28, -B8, -B16, & Bw35
What is the HLA tendency in oral & cutaneous LP?	Oral: HLA-B8 Cutaneous: HLA-Bw35
CLINICAL FEATURES
Where is the locations of LP?	Skin, oral mucosa, any ectodermal-derived tissue (hair, nails, internal & external genitalia, eyes, & esophagus.)
How long is the development of typical LP?	Over the course of weeks.
CUTANEOUS FINDINGS
What are the clinical featurs of LP?	1.          Well-marginated, dull red-violet, flat-topped, polygonal papules. (4”Ps”) 2.          The grouped papules often coalesce into plaques. 3.          Wickham striae, fine, white & adherent reticulate scale (esp. in dermoscopy)
What is the meaning of Wickham striae?	1.          Characteristic features of LP 2.          Correlate with orthokeratosis, epidermal thickening, & an ↑granular layer.
Why does LP have dull red-violet hue?	Combination of vascular dilation & pigment incontinence
Where are the typical locations of LP lesions?	The flexural wrists, arms, legs, proximal thighs, trunk, & neck, symmetrical distribution.
Where are the atypical locations of LP lesions?	Face & palms
Where are the locations of inverse LP ?	Axillae, groin, & inframammary region
What is the most common symptom of LP?	Extreme pruritus (directly correlate with the extent of involvement)
What type of LP affects limited areas but has severe pruritus?	Hypertrophic LP (only lower extremities)
What is the name of trauma-induced disease in acute LP?	Isomorphic (Koebner) phenomenon
What is the reason of isomorphic phenomenon?	Trauma→endogenous peptides (cathelicidin LL-37) or antigens (DNA & RNA)→type I IFNs (-α and -β) →LP
What is the common sequela of LP?	Postinflammatory hyperpigmentation, esp. on darker skin. (hypopigmentation: other diagnosis)
What is the percentage of oral LP? (Adults & children)	Adult: 42-60% (about 1/2) Children: 17-30% (about 1/5)
What is the percentage of hair & nail LP? (Adults & children)	Adult: 2-6% (about 1/20) Children: 0-19% (about 1/10)
CLINICAL VARIANTS
How are LP variant categorized?	According to configuration, morphology, & sites. Configuration: annular LP, linear/ Blachkoid/ zosteriform LP Morphologic appearance: hypertrophic LP, atrophic LP Site of involvements
What are the location of annular LP?	Penis & scrotum
What are the morphology of annular LP?	An arcuate grouping of individual papules→form a ring or expand centrifugally with a central clearing & hyperpigmentation.
What is actinic LP	Annular LP in subtropical zones on sun-exposed, dark-skinned young adults & children.
What is the cause of linear LP?	Trauma induces a row of LP papules.
What is the cause of Blaschkoid LP?	Postzygotic, somatic mutations in susceptibility-associated genes
What is the cause of zosteriform LP?	A viral trigger of disease or an isotopic response related to underlying resident memory cells.
What is the difference between linear & zosteriform LP?	Linear LP does not follow dermatomal lines. Zosteriform LP follow dermatomal lines.
What are the differential diagnoses of linear, Blaschkoid, zosteriform LP?	All segmental diseases: lichen striatus, linear epidermal n., inflammatory linear & verrucal epidermal n., linear psoriasis, & linear Darier dz.
Where are the locations of hypertrophic LP?	Anterior shins & interphalangeal joints.
What are the features of hypertrophic LP?	1.          Thickened, elevated, purple-red, hyperkeratotic plaques & nodules, with follicular accentuation & chalk-like scale. 2.          Highly pruritic, refractory to treatment, & associated with relapse.
What are the differential diagnoses verrucal lesions of hypertrophic LP?	Keratinocyte carcinomas, rupioid psoriasis, rupioid syphilis, reactive arthropathy (Reiter's syndrome), & cutaneous LE
What is the associated disease of hypertrophic LP?	Chronic venous insufficiency
What are the features of atrophic LP?	Oligo-lesional, well-marginated, blue-white papules or plaques with central atrophy.
Where are the locations of atrophic LP?	Proximal lower extremity & trunk
What are the differential diagnoses of atrophic LP?	Lichen sclerosus et atrophicus & mycosis fungoides (MF)
What is the nature of atrophic LP?	Late-stage resolved disease of LP
What is the mechanism of vesiculobullous LP?	Secondary to an exuberant inflammatory response of LP (acute flares) & an exaggerated Max-Joseph space.
What are the features of LP pemphigoides?	1.          Classic LP + lesions of bullous pemphigoid 2.          Bullous pemphigoid antibodies (BP 180 and 230) & immunofluorescence.
What is the mechanism of LP pemphigoides?	LP→exposure of autoantigen→bullous pemphigoid antibody →BP lesions
Where are the locations of vesiculobullous LP?	Lower extremities & oral cavity (became erosion & ulcer).
What are the features of erosive & ulcerative LP?	1.          Erosion & ulcer 2.          Significant pain & scarring 3.          Other ectodermal involvement (scarring alopecia & loss of the toenails) 4.          SCC in chronic lesions of ulcerative oral LP.
Where are the locations of erosive & ulcerative LP?	Feet & oral cavity
What are the 3 major variants of follicular LP?	Lichen planopilaris (LPP), frontal fibrosing alopecia(FFA), & Gram-Little-Piccardi-Lassueur syndrome (GLPLS)
What is the features of LP follicularis tumidus (LPFT)?	Pruritic, red-violet pseudo-tumoral facial & posterior auricular plaques + yellow cysts + LP elsewhere
What are the differential diagnoses of LPFT?	Folliculotropic MF, & cutaneous lupus erythematosus
What are the features of LP pigmentosus (LPP)?	Hyperpigmented, dark-brown macules in sun-exposed & flexural folds, usually in darker skinned individuals.
What is the relationship between LPP & ashy dermatosis(erythema dyschromicum)?	A phenotypic spectrum based on genetic & environmental factors: they have significant overlapping.
What are the features of actinic LP?	1.          Minimally symptomatic 2.          Annular, well-marginated, hyperpigmented brown-violet, flat-topped, plaques with a slightly rolled border 3.          Subtropical zones on sun-exposed, dark-skinned young adults & children of Middle Eastern descent 4.          In the spring & summer months. 5.          Hx: a more brisk LTR relative to LP pigmentosus, vacuolar changes, & pigment incontinence.
Where are the locations of actinic LP?	Face > the dorsal hands, arms, & nape of the neck(sun-exposed skin)
Who predisposes LP of the scalp?	female
What are the 3 variants of LP of the scalp?	LPP, FFA, & GLPLS (the same as follicular LP)
What are the features of classic LPP?	Individual perifollicular hyperkeratosis + diffuse livid erythema→plaques on the scalp→scarring alopecia
Where is the typical location of classic LPP?	Vertex of the scalp
What are the features of LPP on the dermoscope?	Absence of follicular opening, cicatricial white patches, peripilar casts and perifollicular scale, blue-gray dots, perifollicular erythema, & polytrichia (2 or 3 hairs)
What is the features of FFA?	1.          Progressive frontotemporal recession (inflammatory) 2.          Loss of the eyebrows (noninflammatory)
Who predisposes FFA?	Postmenopausal women (but can occur in younger women)
What might be the cause of FFA?	Leave-on facial products, sun-screen, & allergy to fragrances (positive patch test)
What are the features of GLPLS?	Cicatricial alopecia of the scalp, nonscarring alopecia of the axilla & groin, & follicular papules on the trunk & extremities.
What is the end stage of follicular LP?	Pseudopelade of Brocq (it can also be the result of LE, pustular scarring forms of folliculitis, fungal infections, scleroderma, & sarcoidosis.)
Where are the typical locations of mucosal LP?	Mouth or genitalia
What are the types of oral LP?	Reticular(most common), plaque-like, atrophic, papular, erosive or ulcerative, & bullous forms.
What are the locations & symptoms of all the types of oral LP?	1.          Reticular: buccal > tongue> gingiva (asymptomatic) 2.          Erosive & ulcerative: tongue (extremely painful), gingiva (gingival stomatitis or desquamative gingivitis)
What is the difference between oral LP & oral lichenoid reactions (OLRs)	OLRs have an identifiable cause (They are similar clinically & histologically)
Where is the common location or OLRs?	Buccal mucosa adjacent to amalgam dental fillings
What is the result of patch test on the patients with OLRs?	Positive reactions to mercury, gold, & other metals→ negative after the removal of amalgams. (A special site irritant reaction → koebnerization)
What are the features of oral LP on the patients of HIV	1.          Bilateral reticular keratotic or atrophic changes of the buccal mucosa 2.          Lichenoid atrophic patches over the dorsal tongue 3.          Follows zidovudine or ketoconazole intake (a unique drug hypersensitivity)
What is the features of esophageal LP?	1.          proximal esophagus (upper 1/3) 2.          middle-aged women 3.          preceding or concomitant oral LP 4.          progressive dysphagia and odynophagia 5.          lacy white papules, pinpoint erosions, desquamation, pseudomembranes, & stenosis. 6.          Hx: parakeratosis (not in skin LP), epithelial atrophy, & lack of hypergranulosis
What is the percentage of male genitalia involvement of LP?	25% of all male cases
What is the most common pattern & location of LP on male genitalia?	Annular lesions on glans penis
What are the features of anal LP?	Leukokeratosis, hyperkeratosis, fissuring, & erosions
What are the features of vulvar & vaginal LP?	1.          Combined with oral LP (in 25-60% oral LP cases) 2.          Patches of leukoplakia or erythroplakia→erosive & atrophic disease→desquamative vaginitis 3.          Often asymptomatic→burning, itching, painful erosion
What is vulvovaginal gingival syndrome (VVGS)?	Triad of gingival/lingual erythema & erosions, vulvar & vaginal desquamation & erosions. (Also involves skin/scalp/nails/esophagus )
What are the significant long-term sequelae of VVGS?	Fibrosis & stricture of vagina (needs aggressive topical and systemic immunosuppression)
What are the HLA related to VVGS?	Class II HLA DBQ1∗0201 allele
What are the sequelae of conjunctival LP?	Cicatricial conjunctivitis.
What are the differential diagnoses of conjunctival LP?	Paraneoplastic autoimmune multiorgan syndrome & paraneoplastic/cicatricial pemphigoid
How to distinguish conjunctival LP with other cicatricial conjunctivitis?	Direct immunofluorescence, indirect immunofluorescence, & serologies for autoantibodies
What are the signs/symptoms of otic LP?	Otorrhea or external auditory canal stenosis.
What is the long-term sequelae of otic LP?	Progressive hearing loss(involvement of external auditory canal & tympanic membrane)
What are the 3 major forms of nail LP?	Classic nail lichen planus , 20-nail dystrophy, & idiopathic atrophy of the nails.
Which 2 forms of nail LP are common in children?	20-nail dystrophy, & idiopathic atrophy of the nails.
What are the common features of classic nail LP?	Thinning, longitudinal ridging, distal nail splitting (onychoschizia), onycholysis, longitudinal striation with a “sandpaper-like quality” (onychorrhexis), subungual hyperkeratosis, & atrophic or absent nail plates(anonychia)
What is the early finding of nail LP in dermoscopy?	Nail pitting
What is the classic finding in nail LP involving the matrix?	Pterygium or forward growth of the eponychia with adherence to the proximal nail plate (irreversible, loss of nail plate)
What are the common features of 20-nail dystrophy?	Trachyonychia (uniform roughness of the 20 nails), an indolent course.
What are the common features of idiopathic atrophy of the nails?	Abrupt onset & rapidly progressive thinning of the nails→subsequent loss & scarring ± dorsal pterygium
What are the differential diagnosis of nail LP?	Psoriasis, alopecia areata, atopic dermatitis, & rarely immunobullous diseases.
What are the features of inverse LP?	Red-brown, discrete papules & flat-topped plaques at flexural areas
What are the locations of inverse LP?	Flexural areas: axillae, inframammary region, & groin. (antecubital, popliteal, other ectodermal-derived tissues are rare.)
What peoples predispose inverse LP?	Whites, Asians, & Tunisians
What are the differences of LP pigmentosus & inverse LP?	LP pigmentosus inversus: flexural areas, no involvement of sun-exposed areas LP pigmentosus: flexural areas + sun-exposed areas.
Where are the involved areas in those with palmoplantar LP?	1.          Internal plantar arch of feet 2.          Thenar & hypothenar eminence of hands. 3.          Anterior shin & malleoli
What are the features of palmoplantar LP?	Pruritic, red-purple, scaly plaques (a faint purple hue & an inflammatory halo) ± callus-like, yellow, compact keratotic papules/papulonodules on the lateral margins of the fingers & hand surfaces. No Wickham striae.
What are the 4 patterns of palmoplantar LP?	Plaque type, punctate, diffuse keratoderma, & ulcerated
What are the differential diagnoses of palmoplantar LP?	Keratotic papules of palms & soles: psoriasis, warts, calluses, porokeratosis, hyperkeratotic dermatitis, tinea, or secondary syphilis.
What are the features of lichenoid drug eruptions?	Localized or generalized with eczematous papules & plaques with variable degree of desquamation
What are the cause of lichenoid drug eruptions?	Ingestion 1.          Gold salts 2.          β-blackers 3.          Antimalarials 4.          Diuretics (thiazides, furosemide, spironolactone) 5.          Penicillamine 6.          Immune checkpoint inhibotors (17%: pembrolizumab, nivolumab, ipilimumab) Contact or inhalation of certain chemicals. 1.          Color film developers 2.          Dental restoration materials (amalgams: Ag, Hg, Au) 3.          Musk ambrette (合成麝香) 4.          Nickel 5.          Gold 6.          Aminoglycosides
What are the features of lichenoid drug eruptions?	1.          Often with hyperpigmentation & alopecia 2.          Rare Wickham striae 3.          Often symmetrical on the trunk & limbs, less flexural.
What are the common photo-inducer of LP or lichenoid drug eruptions?	1.          5-FU 2.          Carbamazepine, chlorpromazine, diazoxide 3.          Ethambutol 4.          Pyritinol (analog of vitamin B₆) 5.          Quinine (antimalaria ) 6.          Quinidine (class I antiarrhythmic) 7.          Tetracycline 8.          Thiazide 9.          Furosemide
Why is lichenoid drug eruption hard to diagnosed?	The latency period varies from months to >1 year.
How long is the resolution of  lichenoid drug eruption?	3-4 months(related to the severity & extent), but may be years in gold-induced lesions.
What patients may have genetic susceptibility of lichenoid drug eruption?	Recurrent cases and cases involving immune-modulating drugs( INF-α, ipilimumab, pembrolizumab, & nivolumab=melanoma-related)
What are the features of LP-LE?	1.          Overlap of LP & LE (clinical, histology, immunofluorescence) 2.          Red-violet, atrophic patches & plaques + hypopigmentation, telangiectasia, & minimal scale.(The bold is the features of LP) 3.          Some individuals→SLE. 4.          Weakly positive ANA. 5.          Prolonged course & refractory to Tx.
Where are the locations of LE-LP?	The dorsal limbs, esp. hands & nails(anonychia)
What are the features of lichen planus pemphigoides?	1.      LP + BP (LP pemphigoides blisters occur on the lichenoid lesions & normal skin) 2.      Younger age than typical BP 3.      Better prognosis than typical LP 4.      Can be drug-induced.
What is the possible pathogenesis of LP pemphigoides?	The brisk LTR→liquefactive degeneration of keratinocytes→exposure of autoantigens→autoantibody
What is the antigen of LP pemphigoides?	Medical College of Wisconsin domain 4 (MCW-4) of BPAG180
What are the features of keratosis lichenoides chronica (Nekam disease)?	1.          Lichenoid, keratotic papules & plaques 2.          A seborrheic distribution, palms & soles 3.          Folliculo- & infundibulocentric 4.          Linear or reticulate pattern. 5.          Asymptomatic & refractory to treatment 6.          A brisk LTR + parakeratosis + Nφin the crust
Lichenoid Graft versus Host Disease
What is the classic acute GVHD?	Transplant<100 days, a classic (folliculocentric) maculopapular rash; GI s/s; &↑bilirubin (liver).
What is the classic chronic GVHD?	Transplant >100 days, dermatitic, sclerodermoid, or lichenoid eruption
What is the new classification of GVHD?	1.      Acute GVHD: classic, persist, recurrent, or late-onset (after 100 days) 2.      Classic chronic GVHD, and overlap syndromes.
What are the driving cytokine of acute & chronic GVHD ?	Acute: Th2 cytokines Chronic: Th1/Th17 cytokines (IFN-γ– & IL-17)
What are the features of lichenoid GVHD?	1.          Classic lichenoid papules 2.          Prominent follicular involvement of the head & neck & oral involvement. 3.          Onycholysis & cicatricial alopecia
What are the differences between GVHD & LP?	Grossly similar, but GVHD has satellite cell necrosis, plasma cells, & Eφ
What are the features of lichenoid keratosis(LK)?	A single, nonpruritic, brown to red, scaling flat-topped plaque on sun-exposed extremities.
What is the histological feature of LK?	LTRs + parakeratosis or a remnant lentigo, seborrheic keratosis, or actinic keratosis.
What are the features of lichenoid dermatitis?	Nonclassic LTRs + spongiosis ± granuloma
What are the differential diagnoses of lichenoid dermatitis?	Dermatitis, drug eruption, lupus erythematosus, lichen planus, & cutaneous T-cell lymphoma.
RELATED FINDINGS
What is the most common associations of LP?	Liver diseases: autoimmune chronic active hepatitis, primary biliary cirrhosis (PBC), & postviral chronic, active hepatitis.
What are the associated autoimmune dzs of LP?	SLE, Sjögren syndrome, dermatomyositis, vitiligo, & alopecia areata (Taiwanese data)
What is the associated infection of oral LP?	HCV in endemic regions (East & Southeast Asia, South America, the Middle East, & Southern Europe)
Is there association between cutaneous LP and HCV?	No
Is there association between LP & HBV?	No
What is the related HLA of HCV-induced oral LP?	HLA-DR6
What is the common laboratory abnormality in LP?	1.          Dyslipidemia (higher risk of cardiac dz & metabolic syndrome) 2.          Hypothyroidism (in 1/3 LPP)
What is the relationship between LP & lichen sclerosus et atrophicus?	Oral LP→↑lichen sclerosus et atrophicus Lichen sclerosus et atrophicus: no risk of oral LP.
What is the relationship between LP & internal malignancies?	LP can be a manifestation of paraneoplastic autoimmune multiorgan syndrome.