Fitzpatrick's Dermatology in General Medicine
Chapter 145. Cutaneous Lymphoma
鄭煜彬
如果要儘快掌握本章重點，不妨看一下筆者仿照Surgical Recall寫的Dermatological Recall。
- 建議可以先遮住右邊，想一下答案大概是什麼。
- (5)表示答案有五項。(訣)表示有筆者自編的口訣。
- 建議大家先看一下WHO-EORTA的皮膚淋巴瘤分類
Box 145-1 WHO-EORTC Classification of Primary Cutaneous Lymphomas
Cutaneous T-Cell and NK-Cell Lymphomas
Mycosis fungoides
Mycosis fungoides variants and subtypes
Folliculotropic mycosis fungoides
Pagetoid reticulosis
Granulomatous slack skin
Sézary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30-positive lymphoproliferative disorders
Primary cutaneous anaplastic large-cell lymphoma
Lymphomatoid papulosis
Subcutaneous panniculitis-like T-cell lymphoma
Extra-nodal NK/T-cell lymphoma, nasal type
Primary cutaneous peripheral T-cell lymphoma, unspecified
Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)
Cutaneous γ/δ T-cell lymphoma (provisional)
Primary cutaneous CD4+ small or medium-sized pleomorphic T-cell lymphoma (provisional)
Cutaneous B-Cell Lymphomas
Primary cutaneous marginal zone B-cell lymphoma
Primary cutaneous follicle center lymphoma
Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, other
Intravascular large B-cell lymphoma (provisional)
Precursor hematologic neoplasm
CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)
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NK = natural killer; WHO-EORTC = World Health Organization and European Organisation for Research and Treatment of Cancer.
Primary Cutaneous T-Cell Lymphomas
Primary Cutaneous T-Cell Lymphomas
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哪種(類)CTCL最常見?哪種(類)CTCL第二常見?
|
MF/SS最常見，primary cutaneous CD30+ lymphoproliferative disorders(LyP & cALCL)第二。
| ||||||||
CTCL產生的假說與可能原因為何?
|
假說：long-term antigen stimulation
內因：HLA class II molecules
外因：Virus, EBV(Burkitt , hydroa vacciniforme-like )
| ||||||||
CTCL為何初期會局限在表皮?
|
因為有skin-specific homing receptors: cutaneous lymphocyte-associated antigen (CLA) /CCR4/CXCR3，分別可接上postcapillary venules上的E-selectin/ CCL17 /CCL22→
| ||||||||
CTCL細胞在何時何處出現CLA，受什麼細胞誘發?
|
Naive→memory T cells in peripheral skin draining lymph nodes, dendritic cells
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CTCL的哪兩種markers可證明是來自memory T?
|
兩種細胞都有CLA & CD45RO
| ||||||||
和CTCL long-term survival有關的cytokine有哪些?(2)
|
IL-15 & IL-7
| ||||||||
CTCL喪失apoptosis能力和失去哪種分子有關?
|
Fas
| ||||||||
CTCL的Th1/Th2, CD4/CD8 T-cell ratio有何傾向?
|
Th2>Th1, higher CD4/CD8 (less antitumor response)
| ||||||||
Mycosis Fungoides
| |||||||||
MF好發於何人?
|
Male in mid-to-late adulthood
| ||||||||
MF有哪三種stage? 能否共存?
|
patch, plaque, or tumor stage，可以
| ||||||||
Patch stage MF和large parapsoriasis的關係是?
|
幾乎是同一種疾病(邱顯清醫師：我不認識LPP，只認識patch stage MF)
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MF(Patch/Plaque)的臨床特徵為?
|
Intensely pruritic or asymptomatic, single or multiple well defined erythematous(orange to a dusky violet–red), scaly macules, patches or plaque
(少見)purpuric hyperpigmentation or hypopigmentation and poikiloderma.
| ||||||||
MF(nodule) 的臨床特徵為?
|
Reddish brown or purplish red, smooth surfaced, ulcerate and secondarily infected. (more aggressive, Leonine facies)
| ||||||||
那些疾病會造成Leonine facies? (4)
|
Pachydermoperiostosis(HOA), Multicentric Reticulohistiocytosis(MRH), Diffuse Cutaneous Leishmaniasis, Cutaneous lymphoma
| ||||||||
MF好發於何處?
|
Nonsun-exposed sites, with the “bathing trunk” and intertriginous areas, face
| ||||||||
MF有哪兩種特殊的sparing?
|
Islands of uninvolved skin (nappes claires)
Sparing of the frequently folded areas(deck chair or folded luggage sign)
| ||||||||
MF最容易被誤診為?(3)
|
Refractory chronic dermatitis, Psoriasis, tinea corporis
| ||||||||
Erythrodermic MF的定義為何?
|
Involvement of 80% of body surface+ history of preexisting MF (和Sezery不同)
| ||||||||
MF還有哪些全身性症狀?
|
Fever, chills, weight loss, malaise(like other lymphoma), insomnia (severe pruritus), and poor body temperature homeostasis(erythroderma)
| ||||||||
MF的病理特徵為?
|
Cytology: hyperconvoluted cerebriform nuclei
Patch/plaque: band-like infiltrate, epidermotropism, intraepidermal Pautrier's microabscesses
Tumor: nodular infiltrate in the dermis
| ||||||||
MF免疫染色/PCR的特徵為?
|
Mature peripheral T-cell (CD4+) phenotype.
Partial loss of pan-T-cell antigens( CD7,CD3)
Clonal rearrangement of TCR gene as demonstrated by PCR or Southern blot techniques.
| ||||||||
淋巴結侵犯後的MF，五年存活率大約多少?
|
40% (未侵犯可到80-100%)
| ||||||||
Mycosis Fungoides Variants
| |||||||||
Folliculotropic MF好發於何處?何人?
|
Head and neck, adult
| ||||||||
Folliculotropic MF病理上常有哪種物質堆積?
|
Mucinous degeneration(古稱follicular mucinosis or alopecia mucinosis)
| ||||||||
有哪些臨床特徵(2)/著名症狀(3)?
|
Follicular papules/acneiform lesions, indurated plaques/ tumors
Alopecia(Esp. eyebrows), pruritus, & secondary bacterial infections.
| ||||||||
Darker skinned individuals
| |||||||||
Repigmentation.
| |||||||||
Pagetoid reticulosis的定義為何?
|
Localized patches/ plaques with an intraepidermal proliferation of neoplastic cells
| ||||||||
PR的典型長相為?
|
A solitary psoriasiform or hyperkeratotic patch or plaque on the extremities
| ||||||||
PR的行為和MF相比如何?
|
slowly progressive, no extracutaneous dissemination
| ||||||||
廣泛型的PR現在認為是哪種CTCL?
|
Epidermotropic CD8+ T-cell lymphoma
| ||||||||
Granulomatous slack skin好發於何處?
|
Areas of bulky folding of the skin (axillae &groins)
| ||||||||
GSS的病理特徵為?
|
a dense granulomatous infiltrate in the entire dermis, macrophages and multinucleated giant cells + elastolysis
| ||||||||
GSS免疫染色為?
|
CD3+ CD4+ CD8–
| ||||||||
Sézary Syndrome(SS)
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SS的定義為?(3)
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Diffuse erythroderma, generalized lymphadenopathy, and circulating malignant T cells(Sézary cells)
| ||||||||
SS的重要臨床特徵有哪些?
|
Intense pruritus
Erythroderma+severe scaling or fissuring of the palms and soles
Appendix: Alopecia & onychodystrophy
| ||||||||
如何診斷SS?
|
切片不行。Sézary cell > 1,000 cells/mm3 (抹片)或
↑CD4/CD8 ratio (> 10) fluorescence-activated cell-sorting analysis
| ||||||||
SS死亡的主要原因為?
|
Infection(lymphoma會降低免疫力)
| ||||||||
CD30+ Lymphoproliferative Disorders (LyP & ALCL)
| |||||||||
LyP的臨床特徵為?
|
Papulonecrotic lesions: crops of papules/papulonodules with necrotic center
| ||||||||
LyP的行為為?
|
Recurrent, self-healing, elongated course(months or several years)
| ||||||||
LyP的病理特徵與分類為?
|
Wedge-shaped infiltration
| ||||||||
同一病人會有幾種病理分類?
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1-3種。同一病灶在不同時期有不同分類。
| ||||||||
現代醫學可以治癒LyP嗎?
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不行，因LyP不致命，故所有治療均須評量其好處與副作用。
Few, nonscarring lesions: 長期追蹤即可
| ||||||||
LyP有哪些短期有效的治療?
|
Low-dose MTX(5-20mg QW) 最有效，其次是PUVA
| ||||||||
LyP可能伴隨那些淋巴瘤?
| |||||||||
cALCL好發於何人?
|
Male adult
| ||||||||
cALCL的臨床特徵為?
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Solitary or locoregional, larger papulonecrotic lesions(do not remiss)
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cALCL的病理特徵為?
|
A nodular or diffuse nonepidermotropic infiltrate of large cells in dermis. >75% large CD30+ cells
| ||||||||
cALCL有哪些subtypes?(3)
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Anaplastic(最多), Immunoblastic, Pleomorphic(不影響臨床行為與預後)
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cALCL的免疫染色特徵為?
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CD4+ , variable loss of pan-T cell angigen(CD2,3,5,7)
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cALCL和nodal ALCL免疫染色差異為?
|
cCTCL的CD15, EMA, ALK為negative
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cALCL的治療方式為何?
|
Solitary/ localized: excision or radiotherapy
Multiple: PUVA+IFN-α, MTX(20mg/wk), anti-CD30-ab
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cALCL的預後如何?
|
Favorable, 5-year survival rate 90%
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cALCL影響到regional LN時的預後如何?
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不一定較差。(10%患者有此現象)
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Cytotoxic T-cell lymphoma: Subcutaneous Panniculitis-Like T-Cell Lymphoma(SPTCL)& Cutaneous γ/δ T-cell lymphoma(γ/δ)
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SPTCL的臨床特徵為?
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Subcutaneous nodules/plaques, B symptoms(weight loss, fever, & fatigue), a hemophagocytic syndrome
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SPTCL的病理特徵為?
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Lobular panniculitis, pleomorphicαβ T cells(small, medium-sized, or large).
Rimming of fat cells. Vessel invasion.
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SPTCL免疫染色特徵為?
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Cytotoxic T: CD3, CD8, TIA-1, perforin, granzyme B
Memory T: CD45RO
其他: TCR α/β.( γ/δ的另稱Cutaneous γ/δ T-cell lymphoma)
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SPTCL的治療方式為何?
|
Prednisone or multiagent chemotherapy
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SPTCL的預後如何?
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Favorable(5-year survival 85%).可單用prednisone
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γ/δ的別名為?
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SPTCL with a g/d phenotype.
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γ/δ的臨床特徵為?
|
Disseminated ulceronecrotic nodules or tumors,易影響mucosa/ extranodal sites, 不太影響網狀上皮系統(lymph nodes, spleen, or bone marrow)
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γ/δ的病理特徵為?
|
medium-to-largeγ/δcytotoxic T cells(large少見), vessel invasion
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γ/δ有幾種病理pattern?
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Epidermotropic, dermal, and subcutaneous
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γ/δ免疫染色特徵為?
|
Cytotoxic T: TIA-1, perforin, granzyme B
CD4, CD8: 均無,(CD8偶而有)
其他: TCR γ/δ, βF1–,CD56+
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γ/δ的治療與預後如何?
|
multiagent chemotherapy and/or radiation therapy
預後極差(平均活15 months)
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Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type (NKT)
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NKT的臨床特徵為? (請就鼻/皮/血液三方面論述。)
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鼻：lethal midline granuloma
皮：(各種都行) subcutaneous tumors, plaques, ulcers, an exanthematous macules/papules
血液： hemophagocytic syndrome with pancytopenia.
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NKT的病理特徵為?
|
Small, medium, or large NK or cytotoxic T-cell in dermis & subcutis.
Epidermotropism, vessel invasion, extensive necrosis
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NKT免疫染色特徵為?
|
NK: CD56
Cytotoxic T: TIA-1, granzyme B, perforin
EBV(+), CD3– (只有未成熟的CD3ϵ in cytoplasm)
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NKT的治療與預後為何?
|
BM transplantation, lethal(平均活<1年)!
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Epidermotropic CD8+ T-Cell Lymphoma (E8)
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E8的臨床特徵為?
|
(像MF)Hyperkeratotic patches/plaques/papules, or tumor, aggressive
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E8常轉移到何處?
|
甚少到 lymph nodes, 常跑到unusual sites(lung, testis, CNS, oral cavity)
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E8的病理特徵為?
|
Epidermotropic CD8+ cytotoxic T-cell(像MF)
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E8要與那些CTCL鑑別診斷?
|
Pagetoid reticulosis(Acral MF), MF, LyP, and cALCL (主要是前兩個診斷，E8廣泛且嚴重得多)
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E8免疫染色特徵為?
|
Cytotoxic T: CD3, CD8, TIA
Ki67+
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E8的治療與預後如何?
|
multiagent chemotherapy, 甚差(平均活32月)
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Primary cutaneous peripheral T-cell lymphoma, unspecified(PTL) 可略過
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PTL的臨床特徵為?
|
Solitary, localized, or generalized nodules or tumors
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PTL的病理特徵為?
|
Medium-sized(不定) and large-sized(>30%) pleomorphic/immunoblast-like T cells.
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PTL診斷的重點是?
|
排除其他 CTCL
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PTL免疫染色的特徵為何?
|
類似MF: CD4+, variable loss of pan-T-cell antigens
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PTL的治療與預後如何?
|
Multiagent chemotherapy, 極差(5-year survival rate <20%)
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Provisional Entities of CTCL: Pleomorphic Small- or Medium-Sized Cutaneous T-Cell Lymphoma(PSM)病理特徵顯著但臨床不明
| |||||||||
PSM的臨床特徵為?
|
Several red-purplish papules or nodules( no patches & plaques)
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PSM要與那些CTCL鑑別診斷?
|
MF, 尤其是MF-associated follicular mucinosis
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PSM的病理特徵為?
|
(像MF)Small- to medium-sized pleomorphic T-helper-like cells, Epidermotropism(+/-)
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PSM的治療與預後為何?
|
Excision/RT/PUVA+ IFN-α, faverable(60%-90%)
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CTCL小整理
| |||||||||
好發於何人?
|
大多為adult。cALCL好發男性
| ||||||||
好發何處?
|
Lyp, cCTCL, E8, PTL: 任意
SPTCL與γ/δ: extremities(legs)
NKT: nasal cavity>skin
PSM: head & neck
| ||||||||
存活率排行為何?
|
LyP(100%)>ALCL(90%)=MF(100-80%)>SPTCL(85%)>PSM(60-90%)>PTL(<20%)>E8(32m)> γ/δ(15m)>NK/T(<12m)
Mn: Lamps(光明/好的預後)
| ||||||||
細胞的phenotype?
|
Helper: ALCL, MF, PSM, PTL(預後好，除PTL外)
Cytotoxic: SPTCL, E8, γ/δ, NK/T(預後差，除SPTCL外)
| ||||||||
細胞的大小?
|
大中小: LyP, SPTCL, NKT
大中: ALCL,γ/δ, PTL,
中小: PSM
小: MF, E8
| ||||||||
Staging of Cutaneous T-Cell Lymphomas (頂多考到MF/SS)
| |||||||||
Ann Arbor system適合哪種lymphoma?
|
nodal non-Hodgkin lymphomas(CTCL不宜)
| ||||||||
TNM staging適合哪種lymphoma?
|
MF & SS, other CTCL(但MF/SS與other CTCL分法不同)
| ||||||||
Staging要做哪些檢查?
|
Skin PE, CXR, US(abdominal organs and cervical, axillary, and inguinal LN)
Lab: CBC, GPT/GOT, BUN/Crea, LDH, T-cell clonality(TCR rearrangement), CT, skin/LN/viscera biopsy( histologic/ molecular)
| ||||||||
Bone marrow何時要檢查?
|
Blood分級到B2時(≥1,000/μL Sézary cells)
| ||||||||
MF/SS的staging為何?
|
IA: <10%BSA, IB: >10%BSA 小大十
IIA: LN(+)結構在, IIB: tumor 結瘤
IIIA: 紅皮, IIIB: 紅皮+ Sézary cells>5% 紅紅曬
IVA: LN破壞或≥1,000/μL Sézary cells 壞
IVB: metastasis 轉
Mn: 小大十結瘤，紅紅曬壞轉
| ||||||||
Treatment of CTCL
| |
CTCL最重要的surrogate marker for survival為?
|
Tumor burden
|
CTCL治療分為哪兩期?
|
Remission-induction phase & maintenance phase
|
CTCL治療有哪幾種?(3)
|
Skin-directed therapies, biologic response modifiers (BRMs), cytotoxic therapies, & combination therapies
|
各種CTCL的主要治療方法為何?
|
從死亡率低到死亡率高
MF: UVB/PUVA
LyP, cALCL: MTX/excision/PUVA±IFN-α
PSM: Excision/PUVA+ IFN-α/RT
SPTCL: prednisolone or multiagent chemotherapy
PTL: multiagent chemotherapy
E8: multiagent chemotherapy
γ/δ: multiagent chemotherapy and/or RT
NK/T: RT+BM transplantation
|
Skin-directed therapies有哪些?
|
Excision, Spot X-ray therapy, topical carmustine (BCNU), topical bexarotene, topical steroid, topical nitrogen mustard, Electron bean, PUVA/UVB (即從皮膚進去的治療 )
|
Unilesional/Localized CTCL: Skin-Directed Therapy
| |
Distinct demarcated nodules(PSM/ CD30+)適用那些治療?
|
Excision or spot X-ray therapy(快而可靠)
|
Patches and plaques適用那些治療?
|
Spot X-ray therapy, topical carmustine (BCNU), and topical bexarotene(因為面積大而薄)
|
R/T(Spot X-ray therapy)治療有哪些優點?(2)
|
|
R/T (Spot X-ray therapy)治療有何副作用? (2)
|
|
Topical BCNU使用上有何限制?
|
Systemic absorption/toxicity(BM suppression，要定期抽CBC), local irritation(只能局部使用)
|
Topical BCNU有哪些皮膚副作用?(3)
|
hyperpigmentation/ skin thinning/telangiectasias
|
請簡述Topical BCNU如何使用。(註：台灣無，不會考)
|
10-mg-20-mg/100 g ointments( petrolatum)QD
夜擦晨洗，類似Aldara
|
Topical bexarotene gel使用上有何限制?
|
Local irritation(只能局部使用，<15%BSA)
|
請簡述Topical bexarotene gel如何使用。(註：台灣無，不會考)
|
1% gel, nightly lesional applications，一周後BID
|
Disseminated Skin-Limited Disease：要治療全身皮膚+ maintenance therapy
| |
Disseminated MF適合那些治療?(3)
|
光療, topical C/T, & total skin electron-beam R/T(前兩者須maintenance)
|
Disseminated E8 or blastic plasmacytoid dendritic cell neoplasm (BPDCN)等較惡性的淋巴瘤適合那些治療?(1)
|
Polychemotherapy
|
Widespread CD30+適合那種治療?
|
Low dose MTX
|
MF光療有哪些選擇?(3)
|
PUVA(每周3-4次→Q2-4W)>NBUVB(每周3-5次→QW)> BBUVB(照效果排序)
|
PUVA有哪些風險?(2C)
|
Cancer, cataract
|
吃完psoralen要避光幾小時?
|
12小時
|
如何減少PUVA的總劑量?
|
併用IFN-α
|
UVB有哪些風險?(1C)
|
Cancer
|
皮膚淋巴瘤的全身topical C/T要用哪種劑型?
|
Nitrogen mustard (mechlorethamine hydrochloride) QD
Oint: 10 mg/100 g
Aq: 10mg/50ml water
|
使用nitrogen mustard如何保護?
|
戴plastic gloves
|
使用nitrogen mustard有哪些風險?(5)
|
Delayed hypersensitivity reaction, irritant reactions, cancer, hypo-/hyperpigmentation
|
皮膚淋巴瘤的全身R/T要用哪種放射線? 為什麼?
|
Electron-beam, penetrate only to the upper dermis(不影響GI, BM, mucosa…)
|
那些地方R/T容易漏掉，須另外照? (5)
|
palms, soles, scalp, axillae, and perineum
|
R/T時哪兩個地方須特別保護?
|
Eyelid(lead shields/5-mm-thick contact lenses),Nail.
|
R/T的成功關鍵為何?
|
Total radiation dose(>30Gy/3000rad為佳)
|
R/T常見的副作用為何?(4)
|
Alopecia, atrophy of sweat glands / skin, radiodermatitis, edema
|
如何減少R/T副作用?
|
highly fractionated(多分幾次照)
|
Maintenance Therapy and Topical Steroid Therapy
| |
那些治療可用於maintenance Therapy?
| |
PUVA用於MF之Maintenance Tx如何taper?
|
QW(1y)→Q2W(2y) →Q3W(1y) →Q4W(2y)
|
MF幾年沒復發才算cure?
|
8年(皮膚淋巴瘤治療需八年抗戰)
|
懷疑復發可用哪種治療?
|
Topical glucocorticoids(class I)bid(8W)
|
承上，復發要做切片確認時，“wash-out” of steroid要多久?
|
要停steroid 4 weeks
|
Erythrodermaic CTCLs的治療
| |
CTCL引起erythroderma時免疫系統會有那些變化?
|
Immune dysfunctions(易感染) & inflammatory processes
|
哪些治療適合erythrodermaic CTCLs?
|
Oral retinoids, ECP, and subcutaneous injections of IFN-α. (remission大多需要combination, palliation用mono+BRMs即可)
|
Erythrodermatic CTCLs的治療有效指標為?(2)
|
↓BSA, ↓pruritus
|
哪些retinoid適合治療CTCLs?
|
Isotretinoin & bexarotene(high selectivity)
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Bexarotene的治療劑量如何?
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300 mg/m2
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Bexarotene有哪些副作用?(3)
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Hyperlipidemia/hypercholesterolemia, neutropenia(但不會免疫抑制), central hypothyroidism(TSH與T4都低)。
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Bexarotene和那些藥交互作用?(2)
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gemfibrozil & warfarin
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Extracorporal Photochemotherapy(ECP)每次治療約需多久?
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3 hours(類似洗腎)
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ECP大概多久做一次?
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QM, 每次連做兩天(4–6 months見效)
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ECP有效的初始徵象有哪些?
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Return of body hair, loss of rigors(寒顫), and a return of the sweating.
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ECP的治療原理為?
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增強免疫系統對malignant lymphocytes的攻擊力。(<5% malignant lymphocyte 直接被photoinactivated)
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IFN‐α治療的劑量為何?
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Remission-induction: 3MU TIW to 9MU QD
Maintenance: 1MU QD
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IFN -α的副作用為何?
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flu-like illness, depression, neuropathy, dementia, myelopathy, autoimmune thyreoiditis
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IFN –α治療需監控那些Lab?
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CBC & urinanalysis
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有哪些BRMs可治療cutaneous lymphoma? (3)
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DAB389IL-2 (Denileukin Difititox, Ontak®)
Alemtuzumab
Vorinostat
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DAB389IL-2的原理與副作用為何?
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局部IL-2 & diphtheria toxin(DT)合體：接上IL-2受器後，用DT毒殺細胞
Allergic reactions or a capillary-leak syndrome
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Alemtuzumab的原理與副作用為何?
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A humanized monoclonal IgG to CD52，可攻擊malignant lymphocytes
因monocytes, granulocytes, normal lymphocytes也/有CD52，會導致fatal infection
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Vorinostat的原理與副作用為何?
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histone deacetylase inhibitor (HDACI): ↑ histone acetylation→differentiation, cell cycle arrest, & apoptosis
Fatigue, nausea, & thrombocytopenia
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