Squamous cell carcinoma of the skin C44.-

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Dr. med. Ana Luiza Lima, Hadrian Tran

All authors of this article

Last updated on: 20.02.2021

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Synonym(s)

Cornification squamous cell carcinoma; Cutaneous squamous cell carcinoma; SCC; Skin carcinoma; Spinal cell carcinoma; Spinalioma; Spindle cell carcinoma; spinocellular carcinoma; spinocellular epithelioma; squamous cell carcinoma; Squamous cell carcinoma cornifying; Squamous cell carcinoma keratinizing; Squamous cell carcinoma non-cornifying; Squamous cell carcinoma of the skin; Squamous cell carcinoma of the skin cornifying; Sting cell carcinoma

Definition
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Malignant epithelial tumor of the skin with destructive growth and metastasis. Squamous cell carcinoma is the second most common skin tumor after basal cell carcinoma. A metastasis of squamous cell carcinoma is rather rare, it usually occurs first lymphogenically in the regional lymph nodes, later haematogenically.

Classification
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Clinically, squamous cell carcinoma (SCC) of the skin can be divided according to its location into:

Histologically, squamous cell carcinoma (PEK) is divided into:

Occurrence/Epidemiology
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Incidence in Europe: 22-35/100,000 inhabitants/year.

Incidence rate increases by 2-3% annually in North America.

In Norway, incidence rates increased 9-fold for women (annual increases of 5.6%) and 6-fold for men (annual increases of 3.3%) between 1963 and 2011. The highest rate of increase is in the group of 50-70 year-olds (face and capillitium).

Etiopathogenesis
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Multiplicative factors (e.g. hair colour, positive family history, degree of tanning, sun exposure, especially UV rays) play an essential role in the development of the disease:

I. Radiation:

  1. UVB rays induce so-called signature mutations (pyrimidine dimers) in the basal cell layer. In addition, there is an immunosuppressive effect by long-wave UVA rays. Carcinogenesis occurs long before visible lesions develop. In UV-exposed (non-lesional) skin, PEK key mutations (so-called driver mutations) can be detected in about 25% of all cases as the earliest molecular biological correlate of carcinogenesis.
  2. In squamous cell carcinomas,UVA radiation leads to a reduced expression of the Notch signalling pathway. Since the Notch 1 protein (above p21) has a regulating effect on keratinocyte proliferation, this effect is likely to have an impact on local carcinogenesis (Martincorena 2015).

II Chemical carcinogens:

Chemical carcinogens such as aromatic hydrocarbons (see MOAH below) or arsenic are recognised as full-fledged carcinogens in the induction of cutaneous PEKs.

III Human papilloma viruses:

If the carcinoma is not primarily UV-induced (occurs in areas not exposed to light, e.g. genital area, hands and feet), induction with high-risk human papilloma viruses is likely(caution! malignancy increase).

The development of PEK can be correlated with a number of predisposing diseases:

  • Genetically determined syndromes: Xeroderma pigmentosum, oculocutaneous albinism, epidermodysplasia verruciformis, dyskeratosis congenita.
  • Chronic inflammatory diseases: chronic discoid lupus erythematosus, erosive lichen planus mucosae
  • Stagnation dermatoses: chronic lymphedema, chronic leg ulcer
  • Chronic scars: burns, chronic radiation dermatitis

Promoter hypermethylation switches off various (tumour suppressor) genes, such as the FOX-E1 gene (see forkhead box genes below). FOX-E1 codes for a transcription factor that plays a role in cell growth and cell differentiation. Hypermethylation of FOX-E1 leads to its inactivity and has been observed in pancreatic carcinoma, breast carcinoma and spinocellular carcinoma of the skin. Methylation of the promoter region FOX-E1 leads to its inactivation.

Manifestation
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Occurs in patients of higher to advanced age, usually at the bottom of a chronic actinic injury (see below keratosis actinica). The average age of initial manifestation is about 70 years.

Men are affected twice as often as women.

Localization
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Occurs in about 80% of cases in the head area (UV exposure): mainly on the alopecic capillitium, on the red of the lower lip, on the auricles or forehead; less frequently on the back of the hands, fingers (often periungual), sides of the forearm, in the area of the oral mucosa, glans penis, vulva. The occurrence of clinically atypical carcinoma variants, which are summarized under the term verrucous carcinoma (= Ackerman's carcinoma) and which also occur at non-light-exposed sites (HPV induction?), should be noted.

Clinical features
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The clinical picture of squamous cell carcinoma is decisively dependent on the localisation, e.g. whether the skin or mucous membrane is affected.

In the oral mucosa area, squamous cell carcinoma generally presents as leukoplakic rough plaque or as rough, broad, often ulcerated nodules.

The squamous cell carcinoma of the skin is usually painless, skin-coloured or red, usually crusty, coarse humpy, often eroded or ulcerated nodes of coarse consistency. Often, a less strongly keratinized, reddened edge wall, which surrounds a more strongly keratinized centre in the shape of a bowl, is impressive. In the absence of a corneal centre, the carcinoma may present as an ulcer. A coarse-callosity border speaks for the malignant neoplasia.

Wart-like aspects with verrucous corneal deposits are possible. Periungual localization often leads to confusion with banal vulgar warts. Often HPV-16 can be detected in such lesions (genito-digital transmission possible).

In sun-exposed skin areas, the carcinoma may appear under the image of the cornu cutaneum.

Diagnostically problematic may be acral squamous cell carcinomas (e.g. on toes or fingers) with a flat migrating psoriasiform aspect.

The verrucous carcinoma of the sole of the foot often grows endophytically as a result of pressure, and is characterised by superficial ulcerative, painful, flat wart-like plaque, less frequently than nodules.

Histology
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Proliferation of eosinophilic dressings originating from the surface epithelium with variously differentiated keratinocytes infiltrating the different layers of the dermis or also subcutis and the underlying structures in finger-shaped or broad dressings.

  • According to Broders, a distinction is made depending on the proportion of atypical cells:
    • Grade X: no determination possible
    • Grade I: < 25%
    • Grade II: 25-50%
    • Grade III: 50-75%
    • Grade IV: > 75%.

Small epithelial bulbs are often found in the tumor parenchyma, in which concentrically arranged keratinocytes are grouped around a horny bead. In the tumor parenchyma there is a pronounced cell polymorphism with partly largely differentiated keratinocytes and partly dedifferentiated cells with considerable nuclear polymorphism. The cytoplasm of the keratinocytes is usually distinctly eosinophilic. Again and again single cell cornifications are found. Not infrequently, an increasing de-differentiation from top to bottom is observed. In the zones of de-differentiation there are abundant pathological mitoses.

In the AJCC classification (2017), the following histological parameters are considered "high-risk" findings:

  • Tumor thickness >2mm (for head and neck tumors: TD ≥6 mm).
  • Depth of penetration from Clark level 4
  • Degree of dedifferentiation from grade III
  • Perineural invasion (the proportion of carcinomas growing into perineural tissue is between 2.5 and 14%. The feature (especially if the nerve diameter is 0.1mm or >) is associated with a higher rate of local recurrence and lymph node metastasis. Men with tumors in the midface, with recurrent tumors, or with poorly differentiated carcinomas are at risk - Karia PS et al. 2017).
  • Localization: ear and lower lip
  • Immunosuppression
  • Desmoplasia

External therapy
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Local chemotherapy(recommended only for doctors who have great expertise in the treatment of squamous cell carcinoma of the skin!) Curettage with subsequent local therapy with 5-fluorouracil (e.g. Efudix) for 6 weeks should be reserved exclusively (!) for histologically proven in-situ carcinomas. Also photodynamic therapy should only be used for in situ carcinomas (sufficient clinical experience with this modality is mandatory).

Radiation therapy
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  • The clinical results of radiotherapy are equivalent to conventional surgical results. In case of general or local inoperability, expected unfavourable cosmetic results, infestation of large areas of skin or refusal to operate, definitive radiotherapy offers a promising alternative to surgery.
  • Electron or proton radiation: minimum distance 1 cm, ED 2 Gy 5 times/week, GHD 50-70 Gy. On previously damaged skin, cartilage or bone, the dose must be reduced accordingly. Therapy of choice in case of inoperability, non-in-sano-resection, recurrence and/or LK metastases with growth beyond the capsule as well as lymphangiosis carcinomatosa.
  • Postoperatively, radiotherapy improves the local absence of recurrence after R1 and R2 resections and regionally in the case of positive lymph node status. The selection of the appropriate radiation quality depends on the topographical requirements, if necessary the afterloading procedure can also be used. With conventional fractionation with 5 × 2.0 Gy, total doses between 50 Gy (R1), 60-65 Gy (R2) and 70-74 Gy (definitive) are necessary for tumor control.

Internal therapy
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Cytotoxic chemotherapy: Indicated for stage III and IV tumors in patients < 70 years of age with a Karnofsky index > 60%. The aim is palliative, a cure is not expected.

The current guidelines mention cisplatin + 5-FU (or oral analogues) as the therapy of choice for metastatic squamous cell carcinoma.

Since July 2019, cemiplimab (PD-1 inhibitor) has been approved for the treatment of adult patients with metastatic or locally advanced cutaneous PEK who are not eligible for curative surgery or curative radiotherapy. Cemiplimab is administered in fixed doses of 350mg every three weeks and works by inhibiting the PD1-PD1L interaction. Under cemiplimab, 40% of patients achieved remission.

Alternatively, a monotherapy with 5-FU can be administered.

Analternative is monotherapy with methotrexate, which can be administered on an outpatient basis (remission rate: 20-40%).

Alternatively, a combination of cetuximab and paclitaxel. This recommendation was made in analogy to the good experience with PEKs in the head and neck area.

Alternative: Multimodal therapy as a combination of radiotherapy (electron radiation) with chemotherapy, especially indicated for inoperable tumors in the head and neck area.

Alternative (targeted therapy): The epidermal growth factor(EGF-R) expressed on most PEK represents a possible therapeutic target. A first phase II trial with the tyrosinokinase inhibitor of the epidermal growth factor(EGF-receptor) cetuximab in 36 patients achieved complete remission in 5.5%, partial remission in 22.2% and disease stabilization in 41.7% (Maubec 2011).

Experimental: Use of blocking antibodies(nivolumab, pembrolizumab) against the immune checkpoints PD-1 and PDL-1 in several clinical studies. Results remain to be seen.

Operative therapie
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Excision distances (EDF-EADO-EORTC guideline): In principle, an excision with a safety distance of 0.5 cm on all sides is recommended for a low-risk PEK, and with a safety distance of 1.0 cm on all sides for a high-risk PEK. The excision is performed in two stages with temporary defect coverage (e.g. with Syspuderm or Epigard) and should reach into the subcutaneous fatty tissue. Aponeuroses, perichondrium, periosteum can be preserved as long as they have not been infiltrated by the tumor.

Microscopically controlled surgery: Excision of the tumor with a safety distance of 3-5 mm, topographical marking and subsequent complete histological processing of the entire external excised area. Corresponding post-excisions until the excised outer surface is tumour-free.

Adnexal carcinomas require an excision with 2-3 cm safety distance. Micrographic surgery achieves permanent local healing with a relatively high safety margin (88-96%).

In the case of desmoplastic carcinoma, a further safety zone of at least 5 mm is required in addition to the already secured tumour-free zone.

Lymph node dissection: Since squamous cell carcinoma of the skin rarely metastasizes, prophylactic lymph node dissection is not recommended, except in high-risk cases. In high-risk patients, the use of sentinel lymph node biopsy is increasingly being promoted (see carcinoma, cutaneous).

Radiation and cryosurgery: The treatment results of the so-called blind therapy modalities (radiation and cryosurgery) are significantly worse than the surgical procedure. They require special experience by the surgeon. Cryosurgery: (2 cycles, open spray procedure or contact procedure down to -196 °C) should be reserved for precancerous lesions ( keratosis actinica) or in situ carcinomas ( Bowen's disease, erythroplasia) and should only be performed in exceptional cases of invasive squamous cell carcinoma (circumscribed, superficial tumours in older patients).

Progression/forecast
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The prognosis depends on the tumor thickness and localization. It is favourable with adequate surgical procedures. An early metastasis of the penis and vulva carcinomas as well as auricular carcinomas is possible. In the stage of distant metastasis the prognosis of squamous cell carcinoma is mostly infaust!

pT category Definition of the forecast group Metastasis rate
pT1-3a limited to dermis and tumour thickness up to 2 mm 0%
pT1-3b limited to dermis and tumour thickness of more than 2 mm but not more than 6 mm approx. 6 per cent
pT1-3c Invasion of the subcutis and/or tumour thickness more than 6 mm approx. 16%
pT4a for infiltration of deep extradermal structures (T4): 6 mm or less approx. 25%
pT4b in case of infiltration of deep extradermal structures (T4): more than 6 mm up to approx. 40

Other prognostically unfavourable factors (meta-analysis with 17,000 patients):

  • Tumour diameter > 2 cm
  • Invasion beyond the subcutaneous fat layer
  • Rapid growth
  • Recurrence
  • Ulceration
  • Poor differentiation
  • Location: Pinna, temple (Remark: significantly higher risk of regional lymph node metastasis than in carcinomas of other localization), red lips, scrotum, anoderm, apical toe and finger area
  • Location: Mucous membrane of the lips, other mucous membrane of the mouth, glans penis, vulva (metastasis rate: 18-30%)
  • Immunosuppression:PEKs are a typical long-term complication of chronic immunosuppression. In these collectives the incidence of PEKs is 65 times higher (Euvrad 2006).

Sentinel lymph node dissection is recommended for high-risk patients. The procedure is associated with a low concomitant morbidity, comparable to other tumor entities (e.g. malignant melanoma). The rate of false negative lymph node findings is 5%.

Percentages of positive sentinel lymph node findings in relation to the pT category (var. n. Schmitt AR 2014)
pT category % positive sentinel lymph nodes
pT1 0%
pT2 11%
pT4 60%

Prophylaxis
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There is serious evidence that perennial (> 40 years of tea drinking), regular consumption (2 cups and more per day) of black and green tea (both products from the tea plant Camellias sinensis) significantly reduces the risk of carcinoma.

Tables
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Chemotherapy for spinocellular carcinoma

Dosage

Application form

Date

Methotrexate monotherapy

MTX continuously weekly until progression

40 mg/m2

intravenously

Day 1, 8, 15

for mucositis: Leucovorin 4 times 15 mg every 6 hours

cisplatin/doxorubicin

Cisplatin

75 mg/m2

i.v. (infusion over 1-2 hours)

day 1, 22

Doxorubicin

50 mg/m2

intravenously

Day 1, 22

Repeat every 3 weeks

cisplatin/5-fluorouracil

Cisplatin

100 mg/m2

i.v. (infusion over 1-2 hours)

day 1, 22

5-fluorouracil

1000 mg/m2

i.v. (continuous infusion)

Day 1-5, 22-26

Repeat every 3 weeks

cisplatin/5-fluorouracil/bleomycin

Cisplatin

100 mg/m²2

i.v. (infusion over 1-2 hours)

day 1, 22

Bleomycin

15 mg

i.v. (bolus)

Day 1, 22

Bleomycin

16 mg/m2

i.v. (continuous infusion)

Day 1-5, 22-26

5-fluorouracil

650 mg/m2

i.v. (continuous infusion)

Day 1-5, 22-26

Repeat every 3 weeks

Multimodal therapy for spinocellular carcinoma

Cisplatin/5-fluorouracil/radio

Cisplatin

20 mg/m²

i.v. (infusion over 1-2 hours)

day 1-5

5-fluorouracil

200 mg/m²

i.v. (bolus)

Day 1-5

Radio

2 Gy

Electron beam

Day 8-12 and 15-19

Repeat chemotherapy day 22, a total of 4 cycles

Radio over 3 cycles with a GHD of 60 Gy

Literature
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  1. Bivens MM et al (2006) Nonmelanoma skin cancer: is the incidence really increasing among patients younger than 40? A reexamination using 25 years of U.S. outpatient data. Dermatol Surgery 32: 1473-1479
  2. Borradori L et al (2016) Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases. Br J Dermatol doi: 10.1111/bjd.14642.
  3. Chang AL et al(2016) A Case Report of Unresectable Cutaneous Squamous Cell Carcinoma Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor. JAMA Dermatol 152:106-108.
  4. Euvrard S et al.(2006) Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma.Transplantation 81:1093-1100.
  5. Hemminki K et al (2003) Time trends and familial risks in squamous cell carcinoma of the skin. Arch Dermatol 139: 885-889
  6. Hemminki K et al (2003) Familial invasive and in situ squamous cell carcinoma of the skin. Br J Cancer 88: 1375-1380
  7. Johnson TM et al (1992) Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol 26: 467-484
  8. Karia PS et al (2017) Clinical and Incidental Perineural Invasion of Cutaneous Squamous Cell Carcinoma: A Systematic Review and Pooled Analysis of Outcomes Data. JAMA Dermatol 153:781-788.
  9. Koh D et al (2003) Basal cell carcinoma, squamous cell carcinoma and melanoma of the skin: analysis of the Singapore Cancer Registry data 1968-97 Br J Dermatol 148: 1161-1166
  10. Leiter U et al.(2016) Cutaneous squamous cell carcinoma. Dermatologist 67:857-866.
  11. Lobeck A et al (2017) Consideration of the dermatosurgical patient collective at a skin tumor center in Germany. Dermatologist 68: 377-384
  12. Martincorena I et al (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.Science 348:880-886.
  13. Maubec E et al (2011) Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin.J Clin Oncol 29:3419-3426.
  14. Rees JR et al (2007) Tea consumption and basal cell and squamous cell skin cancer: results of a case-control study. J Am Acad Dermatol 56: 781-855
  15. Rinker MH et al (2001) Histologic variants of squamous cell carcinoma of the skin. Cancer Control 8: 354-863
  16. Ross AS et al (2006) Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surgery 32: 1309-1321
  17. Schmitt AR et al (2014) Staging for cutaneous squamous cell carcinoma as a predictor of sentinel lymphnode
    biopsy results: meta-analysis of American Joint Committee on Cancer criteria and a proposed alternative system.JAMA Dermatol 150:19-24.
  18. Thompson AK et al (2016) Risk Factors for Cutaneous Squamous Cell Carcinoma Recurrence, Metastasis, and Disease-Specific Death: A Systematic Review and Meta-analysis. JAMA Dermatol 152:419-428.
  19. Venza I et al (2010) FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma. Br J Dermatol 162: 1093-1097
  20. Wang LE et al (2005) In vitro sensitivity to ultraviolet B light and skin cancer risk: a case-control analysis. J Natl Cancer Inst 97: 1822-1831

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Last updated on: 20.02.2021