Squamous cell carcinoma of the skin C44.-

Malignant epithelial tumor of the skin with destructive growth and metastasis. Squamous cell carcinoma is the second most common malignant skin tumor after basal cell carcinoma. Metastasis of squamous cell carcinoma is rare overall. It usually first occurs lymphogenically into the regional lymph nodes, later hematogenously.

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

• Squamous cell carcinoma in light-exposed areas (classic type)
  • Special form: carcinoma of the lip
• Squamous cell carcinoma in non-light-exposed areas
  • carcinoma of the erythroplasia type
  • Special form: Verrucous carcinoma

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

• Carcinoma in situ of the skin (KIN III)
• Carcinoma in situ of the mucosa ( PIN, AIN, VIN III)
• Spindle cell PE K (syn: pleomorphic squamouscell carcinoma)
• Acantholytic PEK
• Mucinsecreting PEK
• Desmoplastic PEK
• Small cell PEK
• Clear cell PEK
• Lymphoepithelioma-like PEK

Incidence in Europe: 22-35/100,000 population/year.

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

In Norway, between 1963 and 2011, there was a 9-fold increase in incidence rates in women (annual increase rates of 5.6%), and a 6-fold increase in incidence rates in men (annual increase rates of 3.3%). The highest rate of increase is in the 50-70 age group (face and capillitium).

Multiplicative factors (e.g. hair color, positive family history, degree of sun tan, sun exposure esp. UV rays) play a significant role in the development:

I. Radiation:

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

II. chemical carcinogens:

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

III Human papillomaviruses:

In the case of primarily non-UV-induced localization of the carcinoma (occurrence in areas not exposed to light, e.g.genital area, hands and feet), induction with high-risk human papillomaviruses is likely(Cave! Malignancy increase).

The development of PEK may 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.
• congestive dermatoses: chronic lymphedema, chronic leg ulcers
• Chronic scarring: burns, chronic radiation dermatitis

Promoter hypermethylation silences several (tumor suppressor) genes, including the FOX-E1 gene (see forkhead box genes below). FOX-E1 encodes a transcription factor that plays a role in cell growth and differentiation. Hypermethylation of FOX-E1 leads to its inactivity and has been found in pancreatic carcinoma, breast carcinoma, and spinocellular carcinoma of the skin. Methylation of the promoter region FOX-E1 leads to its inactivation.

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.

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.

The clinical picture of squamous cell carcinoma depends crucially on the localization, e.g. whether skin or mucosa is affected.

In the oral mucosa, squamous cell carcinoma generally presents as a leukoplakic dermal plaque or as a dermal broad-based nodule that is frequently ulcerated.

Squamous cell carcinoma of the skin usually presents as a painless, skin-colored or red, usually crusty, coarsely bumpy, often eroded or ulcerated nodule of a rough consistency. Frequently, a less strongly keratinized reddish rim wall, which encloses a more strongly keratinized center in a bowl-shaped manner, is imprinted. In the absence of a horny center, the carcinoma may appear as an ulcer. A derb-callous margin is suggestive of malignant neoplasia.

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

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

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

Verrucous carcinoma of the sole of the foot often grows endophytically due to pressure and presents as a superficially ulcerating, painful, flat wart-like plaque, rarely as nodules.

White circles, keratinous masses, a central corneal plug, hemorrhages, and adenoids can be seen bylight microscopy.

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

Basal cell carcinoma

Melanoma

Keratosis actinica

Chondrodermatitis nodularis chronica helicis

Leukoplakia, oral;

Keratoacanthoma

Pemphigus vegetans

Bowen's disease

syphilitic or tuberculous primary effect

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).

The clinical results of radiotherapy are equivalent to conventional surgical results. In case of general or local inoperability, expected unfavorable cosmetic outcome, involvement of large skin areas or refusal of surgery, definitive radiotherapy offers a promising alternative to surgery.

Electron or proton irradiation: minimum distance 1 cm, ED 2 Gy 5 times/week, GHD 50-70 Gy. On pre-damaged skin, cartilage or bone, the dose should be reduced accordingly. Therapy of choice for inoperability, non-in-sano resections, recurrences and/or LK metastases with cross-capsular growth, and lymphangiosis carcinomatosa.

Postoperatively, radiotherapy improves local freedom from recurrence after R1 and R2 resections and regionally in positive lymph node status. The selection of the appropriate radiation quality depends on the topographic requirements, and afterloading may be used if necessary. Conventional fractionation with 5 × 2.0 Gy requires total doses between 50 Gy (R1), 60-65 Gy (R2), and 70-74 Gy (definitive) for tumor control.

Cytotoxic chemotherapy: Indicated for stage III and IV tumors in pat. < 70 years with a Karnofsky index > 60%. The objective is palliative, cure is not expected.

Current guidelines mention cisplatin + 5-FU (or oral analogues) as first-line therapy for metastatic squamous cell carcinoma.

As of July 2019, cemiplimab (PD-1 inhibitor; Libtayo®) is approved for the treatment of adult patients with metastatic or locally advanced cutaneous PEK who are ineligible for curative surgery or curative radiotherapy. Cemiplimab is approved in intravenous fixed doses of 350mg every three weeks for 30 minutes and acts via inhibition of the PD1-PD1L interaction. With cemiplimab, 40% of patients achieved remission.

Alternatively, monotherapy with 5-FU may be used.

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

Alternative: combination of cetuximab and paclitaxel. This recommendation was given in analogy to the good experience with PEKs in the head and neck area.

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

Alternative ( Targeted therapy): Epidermal growth factor(EGF-R) expressed on most PEK represents a possible therapeutic target. An initial phase II trial of the tyrosinokinase inhibitor of epidermal growth receptor(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 immune checkpoints PD-1 and PDL-1 in several clinical trials. Results remain to be seen.

Excision distances (EDF-EADO-EORTC guideline): In principle, 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. Excision is performed bilaterally with temporary defect coverage (e.g., with Syspuderm or Epigard) and should extend into the subcutaneous fat tissue. Aponeuroses, perichondrium, periosteum can be preserved as far as they have not been infiltrated by the tumor.

Microscopically controlled surgery: excision of the tumor with 3-5 mm safety margin, topographic marking and subsequent complete histological workup of the entire excidate outer surface. Appropriate re-excisions until the excidate outer surface is tumor-free.

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

In the case of desmoplastic carcinoma, a further safety zone of at least 5 mm is required beyond the already secured tumor-free zone or, if available, a gap-free margin control should be performed here. In addition, immunohistochemical staining should be performed: Schweinzer et al. demonstrated that 27.8% of margins found to be in sano by HE in desmoplastic squamous cell carcinomas showed tumor remnants in pancytokeratin staining (AE1/AE3).

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, sentinel lymph node biopsy is possible (see Carcinoma, cutaneous). Here, however, based on recent data, the indication should be considered very strictly, as so far no advantage in terms of survival or locoregional recurrence has been shown after sentinel lymph node biopsy compared with control groups.

Radiosurgery, cryosurgery: The treatment results of the so-called blind therapy modalities (radiosurgery, 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 be performed in invasive squamous cell carcinoma only in exceptional cases (circumscribed, superficial tumors in patients of advanced age).

The prognosis depends on tumor thickness and localization. It is favorable with an adequate surgical approach. Early metastasis of penile and vulvar carcinomas and auricular carcinomas is possible. In the stage of distant metastasis, the prognosis of squamous cell carcinoma is mostly infaust!

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

• Tumor diameter > 2 cm
• Invasion beyond the subcutaneous fat layer
• Rapid growth
• Recurrence
• Ulceration
• Poor differentiation
• Localization: auricle, temple (note: significantly greater risk of regional lymph node metastasis than carcinomas of other localization), labial red, scrotum, anoderm, apical toe and finger area
• Localization: mucosa of lips, other oral mucosa, glans penis, vulva (metastasis rate: 18-30%).
• Immunosuppression:PEKs are a typical long-term complication of chronic immunosuppression. In these collectives, there is a 65-fold increased incidence of PEKs (Euvrad 2006).

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

There is serious evidence that multi-year (> 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 .

Light protection. Avoidance of direct sunlight, light protection preparations with high light protection, avoidance of photosensitizing or phototoxic drugs, e.g. hydrochlorothiazide.

Chemotherapy for spinocellular carcinoma

Multimodal therapy for spinocellular carcinoma

Follow-up of patients with cutaneous PEK (R0-resistant) should be offered at risk-adjusted intervals according to the following schedule:

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 Surg 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. Kofler L et al (2021) Sentinel lymph node biopsy for high-thickness cutaneous squamous cell carcinoma. Arch Dermatol Res 313:119-126.
10. 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.
11. Leiter U et al.(2016) Cutaneous squamous cell carcinoma. Dermatol 67:857-866.
12. Lobeck A et al. (2017) Review of the dermatosurgical patient population at a skin tumor center in Germany. Dermatologist 68: 377-384
13. Martincorena I et al (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.Science 348:880-886.
14. 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.
15. 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.
16. Rinker MH et al (2001) Histologic variants of squamous cell carcinoma of the skin. Cancer Control 8: 354-863
17. Ross AS et al (2006) Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg 32: 1309-1321
18. Schmitt AR et al. (2014) Staging for cutaneous squamous cell carcinoma as a predictor of sentinel lymph node biopsy
19. node biopsy results: meta-analysis of American Joint Committee on Cancer criteria and a proposed alternative system.JAMA Dermatol 150:19-24.
20. Schweinzer K et al. ( 2017) Cytokeratin AE1/AE3 immunostaining and 3D-histology: improvement of diagnosis in desmoplastic squamous cell carcinoma of the skin. Arch Dermatol Res 309:43-46.
21. 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.
22. Venza I et al (2010) FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma. Br J Dermatol 162: 1093-1097.
23. 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