[考生加油] Dermatological Recall: Chapter 112 :: Squamous Cell Carcinoma and Keratoacanthoma

鱗狀細胞癌是第二常見的皮膚癌，臨床上看起來是一塊堅硬、角質增生的斑塊或結節，可能伴隨潰瘍。這種皮膚癌處理起來要比較積極，不然一旦轉移就比較不好處理，不像第一常見的基底細胞癌就算拖了很多年也不至於致命。

Chapter 112 :: Squamous Cell Carcinoma and Keratoacanthoma

:: Anke S. Lonsdorf & Eva N. Hadaschik

鄭煜彬(20200320)

EPIDEMIOLOGY & DEMOGRAPHICS
What is the most common & costly malignancy in European ancestry?	Squamous cell carcinoma (SCC)
What patient is the high-risk populations of SCC?	Patients with immunosuppression
What is the rank of skin cancer?	1st: BCC, 2nd: SCC
What is the most common skin cancer in the immunosuppressed?	SCC
INCIDENCE
Why does the incidence of SCC rise steadily?	A greater lifetime UVR exposure, greater longevity, ozone depletion, & ↑voluntary exposure to UVR
MORBIDITY & MORTALITY
What is the major cause of deaths in non-melanoma skin cancers (NMSCs)?	SCC (with metastasis)
What is the prognosis of majority of SCC?	Most are early-stage disease and treated & cured with surgery. (Excellent prognosis)
What is the rate of metastasis of SCC?	5-year metastatic rate is 5% (low), predominantly nodal metastasis
What is the geographic factors of SCC?	UV irradiation (inverse association with latitude, association with altitude)
What is the common onset age of SCC?	60 years of age and older. (the incidence ↑ with age)
Why does the incidence of SCC increase recently?	↑voluntary exposure to UVR→↑cumulative life- time exposure to UVR
Which sex has lower incidence of SCC?	Female (less livetime UVR exposure + less genetic susceptibility to UV-induced immunosuppression)
What people had risk of SCC?	Red hair, blue eyes, & fair complexion (Eg. 哈利波特的榮恩．衛斯理)
ETIOLOGY AND PATHOGENESIS
What kinds of genetic defects may predispose SCC?  (4)	1.      Repair or stability of genome 2.      Function of melanin 3.      Immunity 4.      Structure of the skin
What are the SCC syndromes related to repair or stability of genome? (6)	Bloom syndrome (BLM/RECQL3, Chromosomal stability) Dyskeratosis congenita(DKC1/TERC, telomere homeostasis & telomerase trafficking ) Fanconi syndrome (FANC A~S, DNA crosslink repair) Rothmund-Thomson syndrome (RECQL4, Chromosomal stability) Werner syndrome (WRN/RECQL2, Chromosomal stability) Xeroderma pigmentosum & variants(XP A~G, nucleotide excision repair, error-prone DNA polymerase)
What are the SCC syndromes related to the function of melanin? (5)	Albinism (TYR, OCA2…, melanin synthesis) Chediak-Higashi syndrome (LYST, lysosomal transport) Elejalde syndrome (MYO5A, pigment granule transport) Griscelli syndrome (MYO5A/RAB27A/MLPH, pigment granule transport) Hermansky-Pudlak syndrome (HPS 1~8, melanosomal & lysosomal transport)
What are the SCC syndromes related to immunity? (1)	Epidermodysplasia verruciformis (EVER1/TMC6, EVER2/TMC8)
What are the SCC syndromes related to the structures of the skin? (2)	Recessive Dystrophic epidermolysis bullosa (COL7A1) Junctional epidermolysis bullosa (LAMA3, LAMB3, LAMC2, COL17A1)
What are the keratoacanthoma-related syndromes?	Muir-Torre syndrome (MSH1, 2, DNA mismatch repair) Ferguson-Smith syndrome (TGFBR1, TGF ß 1 receptor 1 signaling)
	(除JEB外，基因部分記開頭第一個就好)
PRECURSOR LESIONS
What is the original cell of SCC?	Basal keratinocytes of the interfollicular epidermis
What are the preinvasive lesions of SCC? (4)	Bowen disease, Actinic keratosis (AK), bowenoid papulosis, erythroplasia of Queyrat.
What is the cumulative life-time risk of SCC among patients with multiple AK?	6-10% (<10%)
What is the difference between keratoacanthoma & typical SCC?	It has rapid growth phase and subsequent slow spontaneous regression. (It is a midpoint between a viral acanthoma and SCC)
RISK FACTORS
What are the risk factors of SCC?	UVR/radiation, physical & chemical carcinogens, genetic predisposition, immunosuppression, drugs, viral infection, chronic inflammation, & chronic injury of the skin.
What is the most important environmental risk factor of SCC?	UVR=UVA+UVB (class I carcinogen→initiation, promotion, & progression of squamous carcinogenesis)
What is the specific UV signature mutations of UVB?	Characteristic C-T and CC-TT dipyrimidine transitions (direct damage)
What is the mechanism of UVA carcinogenesis?	Photooxidative stress-mediated genotoxicity (indirect damage)
How does UVR promote SCC development? (other than “induce”)	Immuno-suppression & modulation: depletion of Langerhans cells, improper antigen presentation in LN, ↑Treg, ↑Th2
What are the genetic predisposition of SCC?	Light skin complexion (skin photo types I & II), variations in the melanocortin-1 receptor, polymorphisms in pigmentation genes, & all SCC syndromes mentioned before.
What are the famous physical & chemical carcinogens of SCC?	Arsenic, cutting oils & chimney sweeps(polycyclic aromatic hydrocarbons of coal tar), ionizing irradiation & UVR,
What patients have higher risk of SCC? (5)	Patients with immunosuppression: l   solid-organ transplantation recipients (OTRs) l   hematopoietic stem-cell transplant recipients l   Patients with HIV l   Patients with a history of autoimmune or rheumatoid disease, l   Chronic lymphatic leukemia (CLL)
What kinds of transplantation have higher risk of SCC?	Heart/lung> kidney/liver (because of intensive immunosuppressive regimens & older age)
What drugs may increase SCC risk?	l   Photosensitizing drugs (eg, antibiotics, fluoroquinolone, triazole antifungals) l   psoralen plus UVA l   azathioprine plus UVA (Interference with cellular DNA repair, induction of oxidative stress, & ↑ p53 oncogene) l   Cyclosporine l   BRAF-inhibitors (vemurafenib & dabrafenib, for metastatic melanoma) l   Kinase inhibitor sorafenib l   hedgehog pathway inhibitor (vismodegib, for unresectable BCC
What kind of drugs decrease SCC risk in transplantation?	Rapamycin (mTOR) inhibitor sirolimus (interrupt PI3K-AKT pathway→↓EGFR signaling)
What virus may induce skin SCC?	HPV(genus type beta, mucosal ca.: α-HPV), MCPyV polyoma virus
What lesion has higher prevalence of HPV DNA?	Actinic keratosis (sun-exposed skin)
Why does β-HPV usually induces skin SCC on the sun-exposed skin?	l   β-HPV is unable to integrate into the cellular DNA but disturbs the repair under UV l   UV has immunosuppressive effect on skin→ predisposing for HPV infection
What is the most famous genodermatosis with HPV infection and SCC?	Epidermodysplasia verruciformis (AR, HP-5 & 8, SCC at sun-exposed areas)
What is the oncogenic proteins of β-HPV?	E6 & E7: impair p53
What are the common physical injury predisposing SCC?	Burn scars & radiation dermatitis.
What diseases induce chronic inflammation/injury/ulcer predisposing SCC?	Discoid lupus erythematodes, lichen ruber mucosae, lichen sclerosus, lupus vulgaris & dystrophic epidermolysis bullosa(RDEB).
What are the common mutated genes in skin SCC?	tumor-suppressor gene p53 (TP53) 3 Ras genes (9% Hras, 7% Nras, 5% Kras) EGFR(advanced SCC)
CLINICAL PRESENTATION CLASSICAL PRESENTATION
Where is the location of SCC?	Sun-exposed areas: face (nose & cheeks), head, neck, forearms & dorsum of the hands.
What is the relationship between AK, Bowen dz, & SCC?	SCCs usually develop on a background of AK or Bowen disease as precursor lesions
What is the “field cancerization” of SCC?	Numerous precursor lesions of Bowen dz on UV-damaged skin. (High risk for progression to SCC. de novo formation on undamaged skin is rare)
What is the clinical features of SCC?	Slowly enlarging, firm, skin-colored to erythematous plaques or nodules with marked hyperkeratosis.
What are the 3 growth patterns of SCC?	Ulceration, exophytic, or infiltrative
SPECIAL LOCATIONS ORAL SQUAMOUS CELL CARCINOMA
Where does oral SCC develop?	Normal mucosa, or precursor lesions.
What are the precursor lesions of oral SCC?	leukoplakia, erythroplakia, or leukoerythroplakia
What is the features of oral SCC?	Whitish surface or ulcers with elevated indurated borders
What are the 2 growth patterns of oral SCC?	Exophytic or endophytic patterns + subsequent ulcer
SCC OF THE LOWER LIP
Where is the common location of lip SCC?	Lower lip (> upper lip)
Where is the typical sun terrace of face?	Lower lip, nose & cheeks
VERRUCOUS SCC
What is the features of verrucous SCC?	A slowly growing ulcerated plaque or an exophytic cauliflower-like slowly growing tumor.
Where is the locations and related-names of verrucous SCC?	l   oral cavity (oral florid papillomatosis) l   genitoanal region (giant condyloma acuminatum = Buschke-Löwenstein tumor) l   plantar skin (epithelioma cuniculatum) l   amputation stumps.
KERATOACANTHOMA(KA)
What is the nature of KA?	Highly differentiated SCC
What is the features of KA?	l   A sharply circumscribed firm symmetric nodule with the characteristic central horn-filled crater. l   Erupts rapidly within a few weeks & has the ability to spontaneously regress
Where is the location of KA?	On the head & sun-exposed areas of the limbs
What are the clinical variants of KA? (8)	grouped KA, subungual KA, intraoral KA, giant KA, KA centrifugum marginatum, multiple KA of the Ferguson-Smith type, eruptive KA of Grzy- bowski, & KA associated with Muir-Torre syn.
DIAGNOSIS
What are the items included in the standard histopathology?	l   Histologic subtype (acantholytic, spindle cell, verrucous, or desmoplastic type) l   Grade of differentiation (G1 to G4) l   Maximum vertical tumor diameter (in mm) l   Extent of dermal invasion (Clark level) l   Perineural, vascular, or lymphatic invasion. l   Free margin & minimum distance to margin
GENERAL CONSIDERATIONS IN HISTOPATHOLOGY
What is the difference between SCC in situ & invasive SCC?	The growth of atypical keratinocytes beyond the basement membrane into the dermis.
What are the major immunohistochemical markers of SCC?	Cytokeratins (not obvious in tumors with little or no keratinization)
BASIC HISTOPATHOLOGIC FEATURES OF SCC
What is the histologic features of SCC?	Atypical keratinocytes originating in the epidermis & infiltrating into the dermis
What is the histologic features of well-differentiated SCC?	Minimal pleomorphism, prominent keratinization, parakeratosis, individual cell dyskeratosis, & horn pearl formation
What is the histologic features of poor-differentiated SCC?	Pleomorphic nuclei with a high degree of atypia, frequent mitoses, & very few areas of keratinization
HISTOPATHOLOGIC VARIANTS OF SCC WITH DIFFERENTIAL DIAGNOSIS
What are the variants of SCC?	Spindle-cell SCC, acantholytic (adenoid) SCC,
What are the clinical & histologic features of spindle-cell SCC?	l   A relatively rare form l   Skin of the elderly l   Sun-exposed areas or radiation port.  l   Spindled morphology & lack of keratinization
What are the common spindle-cell neoplasms?	Atypical fibroxanthoma, spindle-cell melanoma, & sarcomas
What are the clinical & histologic features of acantholytic SCC?	l   More metastasis l   Extensive acantholysis of the atypical keratinocytes→pseudoglandular structures
What are the clinical & histologic features of verrucous SCC?	l   A well-differentiated variant l   Slowly grows & locally destructive, low metastatic potential l   Need a large, deep incisional biopsy l   Superficial part: like verrucae (parakeratosis, acanthosis, & prominent s. granulosum) l   Deeper part: broad, deep, downward proliferations of light eosinophilic, monomorphic well-differentiated keratinocytes with small nuclei & noninvasive pushing borders.
What are the clinical & histologic features of desmoplastic SCC?	l   A highly infiltrative growth pattern with abundant mucinous stroma l   Perineural or perivascular infiltration, l   A high rate of recurrence & metastases.
What are the clinical & histologic features of KA?	l   Symmetric tumor (scanning view is necessary for diagnosis) l   Markedly hyperplastic epithelium of early lesions l   Central keratotic plug surrounded by a well-differentiated proliferation of squamous epithelium in later stages. l   Hypoplastic epithelium with central crater in regressing lesions. l   Large strands of monomorphic keratinocytes + eosinophilic cytoplasm & small nuclei +a surrounding inflammatory infiltrate (lymphocytes, Eφ, & Nφ)
GRADING
What is the meaning of the classification system of the American Joint Committee on Cancer (AJCC)?	It reflects the degree of cellular differentiation, which is a high-risk feature for staging.
What is the scales of the classification system of AJCC ?	Based on increasing percentages of undifferentiated cells G1 = well differentiated G2 = moderately differentiated G3 = poorly differentiated G4 = undifferentiated grade Gx = grade cannot be assessed.
STAGING
What should be examined in the staging of cutaneous SCC?	l   A complete examination of the entire skin l   Nodal involvement of the regional LNs by palpation and/or ultrasound examination.
What is the current staging system of cutaneous SCC?	TNM (tumor, node, metastasis) system of the Union International Contrele Cancer (UICC, 2009) and the AJCC (2010)
What are the high-risk histologic features of SCC?	>2 mm thickness, Clark level >IV, perineural invasion, primary site being the lip or ear, & poorly or undifferentiated tumor
What is the definition of T1-4?	T1: tumors < 2 cm (greatest dimension) & <2 high-risk features T2: tumors > 2 cm (greatest dimension) & tumors of any size with ≧2 high-risk features. T3: Tumor with invasion of maxilla, mandible, orbit, or temporal bone T4: Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of skull base (請以表格為主，內文有誤)
What is the definition of N1, N2a, N2b, N2c, N3?	Based on number, localization and size
What is the meaning of lymph node involvement?	↑the risk of recurrence & mortality
How can you confirm the nodal involvement histologically?	Fine-needle aspiration or lymph node biopsy
What is definition of M0 & M1?	M0: no distant metastases M1: distant metastases
DIFFERENTIAL DIAGNOSES
What are differential diagnoses of cutaneous SCC?	Hyperkeratotic seborrheic keratoses; viral acanthoma; viral warts; & acanthoma fissuratum.
What is the differential diagnoses of cutaneous SCC with ulcerative or infiltrative growth?	Scars, DLE, lichen planus, & morpheaform BCC
What is the differential diagnoses of cutaneous SCC on the ear?	DLE & chondrodermatitis nodularis chronica helicis
MANAGEMENT
Why is the surgical resection or a biopsy necessary for the management of SCC?	It can confirm the invasiveness (according the subtype, grading, & staging) before any therapeutic intervention other than surgery.
SURGERY
What is the major treatment for primary SCC?	Surgical excision, esp. Mohs surgery
How much is the cure rate of surgery of SCC?	95%
What are the advantages of surgery in SCC?	l   Free margin: totally clearance l   Histopathologic characterization
How many mms is the safe margin for local, low-risk SCCs?	4- to 6-mm
How to treat local in-transit metastasis of SCC?	l   Removed by wide surgical excision l   Treated by irradiation of a wide field around the primary lesion.
How to treat nodal metastasis?	Lymph node dissection, radiation, or a combination of both.
NONSURGICAL INTERVENTION
What are the topical therapies of invasive SCC?	Topical imiquimod, topical or intralesional 5-fluoruracil, cryotherapy, & photodynamic therapy
What is the status of topical therapies of invasive SCC?	They are not an appropriate treatment modality for invasive SCC!
What are the choices for locally advanced, unresectable or metastatic SCC?	Radiation therapy, chemotherapy or targeted therapy.
RADIATION THERAPY
When is radiation therapy considered for invasive SCC?	l   SCCs at problematic locations for surgery l   Inoperable, local in-transit metastasis l   After excision of potentially aggressive local tumors (risky subtypes, high grading, extensive/perineural involvement) l   Clear margins cannot be achieved l   Alternative treatment of superficially invasive, small SCCs in low-risk areas
What is the role of sentinel LN biopsy & elective prophylactic LN dissection in the Tx of invasive SCC?	No conclusive evidence of its prognostic or therapeutic value.
SYSTEMIC TREATMENT OF LOCALLY ADVANCED AND METASTATIC SCC
What are the choices of the chemotherapy in SCC?	Platinum-based chemotherapeutic regimens, 5-fluorouracil/capecitabine, or monotherapy/chemo therapy with methotrexate.
What are the choices of the targeted therapy in SCC?	EGFR inhibitors: small molecules (erlotinib & gefitinib), antibodies(cetuximab & panitumumab)
When should the targeted therapy use?	Advanced SCC beyond radiotherapy & conventional chemotherapy (off-label use)
PROGNOSIS
How about the prognosis of the majority of SCCs?	They are low risk and in early stage, resulting in a high cure rate and excellent prognosis.
How about the prognosis of locally advanced SCC or progressive disease after first-line surgical therapy?	Poor (overall survival of only 10.9 months)
What kind of patients has poorer prognosis?	Immunosuppressed patients(↑tumor burden, aggressive tumor behavior, metastatic disease, & disease-specific death from SCC.)
What is the most common fatal skin malignancy in organ transplantation recipient?	SCC(> 60% of deaths from all skin malignancies, but death rate is only 5%)
LOCAL RECURRENCE
What is the event before metastasis?	Local recurrence at the site of the primary lesion
How can you lower the local recurrence?	Perform Mohs surgery
METASTASIS
What are the risk factors of recurrence & metastasis in NCCN guideline? (13)	l   Area H (“T-shaped” mask areas(五官分布的範圍), genitalia, hands, & feet) l   Area M (cheeks, forehead, scalp, neck, & pretibial) ≧10mm l   Area L (trunk & extremities)≧20mm l   Poorly defined borders l   Recurrent lesions l   Immunosuppression l   Site of prior RT or chronic inflammatory process l   Rapid growing l   Neurologic symptoms l   Poorly differentiated l   Acantholytic (adenoid), adenosquanous (mucin production), desmoplastic, metaplastic (carcinosarcomatous) subtypes l   Thickness > 6mm or invasion beyond subcutaneous fat. l   Perineural, lymphatic, or vascular involvement
What are the histological subtypes with high risk? (4)	Acantholytic (adenoid), adenosquanous (mucin production), desmoplastic, metaplastic (carcinosarcomatous) subtypes
What is the meaning of “Breslow thickness > 2 mm”?	A high risk of metastasis and local recurrence(NCCN guideline: >6mm)
AFTERCARE
What is the standardized followup schedules for patients with SCC?	It does not exist.
Who should be followed up closely?	Immunosuppressed patients, & lesions with high risks.
What should we do for the immunosuppressed?	Dermatologic surveillance, skin cancer prevention strategies, & the timely treatment of precancerous & in situ lesions
When are the locally recurring & metastatic SCCs detected?	70-80% are detected within 2 years after primary diagnosis.
What is the most common secondary skin cancers of cutaneous SCC?	Secondary SCC & BCC (all SCC patients are at risk of additional secondary SCC & BCC )
PREVENTION
What are the key factors for the prevention of SCC? .	Sun avoidance & close dermatologic surveillance of high-risk individuals
What is the choices of chemoprevention of SCC? (2)	Niacinamide (vitamin B3) & retinoids (vitamin A derivatives)
How does niacinamide prevent SCC?	l   Niacinamide→nicotinamide adenine dinucleotide→nicotinamide adenine trinucleotide→improve UV-induced cellular nicotinamide adenine trinucleotide loss(& repair of DNA damage) l   Promotes of epidermal differentiation l   Inhibits UV-induced immunosuppression & photocarcinogenesis
How does retinoids prevent SCC?	It promotes normal epidermal differentiation.
How can you modify the immunosuppressive agents in the case of SCC?	l   Dose reduction of the immunosuppressive agents l   Minimizing the doses of calcineurin inhibitors and/or antimetabolites l   Shifting the agents to mTOR inhibitors.