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SQUAMOUS CELL CARCINOMA

Introduction

Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor that represents the second leading cause of skin cancer, and its incidence appears to be rising. Although several factors may contribute to the development of cSCC, increased exposure to solar ultraviolet radiation (UVR) that leads to actinic skin damage is its primary cause. White individuals with fair skin—especially those who spend extensive periods of time in the sun and/or who live in close proximity to the equator—as well as individuals who use artificial tanning beds all have a higher risk of acquiring cSCC. A cSCC appears as a red, rough, scaly skin patch or non-healing ulcer, and it has the potential to metastasize to other organs in the body, including the lymph nodes. Most cases of cSCC are low-risk and can be treated effectively with dermatological procedures such as radiation therapy, chemotherapy, electrodissection and curettage, photodynamic therapy, and cryosurgery.1-3,18  High grade cSCC lesions >2 cm, depth > 2 mm, and growing rapidly require surgical excision.  Low grade cSSC can also be treated with surgical excision.18
 

Pathophysiology

  • Although a range of factors—including immunosuppression, burns, and chronic infection—may contribute to the development of cSCC, the majority of cases are associated with actinic skin damage, and its main external cause is solar UVR1
  • There is a strong relationship between level of cumulative sun exposure and cSCC risk
    • In addition to fair-skinned individuals, albinos and those with xeroderma pigmentosum are at an increased risk for cSCC
    • There is significant geographic variation in cSCC occurrence that is primarily explained by ambient UVR light exposure, as incidence rates are higher with closer proximity to the equator3
    • Exposure to artificial UVR from indoor tanning facilities like sunbeds is also significantly associated with cSCC development, with the highest risks being found in those exposed before 25 years of age1
    • One of the strongest predictors of cSCC development in previously unaffected people is the presence of actinic keratoses (AKs), or solar keratoses, caused by cumulative sun exposure and occur mostly on the head and neck, dorsum of the hands, and forearms in older, pale-skinned individuals; however, only a small proportion of AKs are cSCC precursors, and the rate of their malignant transformation is unclear1
    • Immunosuppression is another major risk factor for cSCC, and organ transplant recipients, those diagnosed with HIV/AIDS, non-Hodgkin lymphoma, and chronic lymphocytic leukemia all appear to have increased rates of cSCC
    • Use of glucocorticoids has been reported to increase the risk of cSCC by approximately twofold1
    • Smoking has also been shown to be an important risk factor for the development of SCC3
    • Some cases of cSCC develop de novo, as a result of previous exposure to ionizing radiation or arsenic, within chronic wounds, scars, burns, ulcers or sinus tracts, and from pre-existing lesions such as Bowen's disease2  Unlike conventional cSCCs, which tend to occur on the face, neck, hands, and other sun-damage prone areas, de novo cSCCs are most commonly found on the lower extremities4

While cSCC of hand accounts for as much as 90% of the malignancies of hand, SCCNU squamous cell carcinoma of nail unit can also affect the digits of the hand but is very rare.  SCCNU can be difficult to diagnose because it may present as a chronic infection or even a wart of nail bed.  SCCNU invades the bone about 50% of the time.  With metatasis to the lung fatality rates can approach 40%.

Related Anatomy (cSCC)

  • The vast majority of Bowen’s disease cases (~72%) occur on sun-exposed surfaces such as the head, neck, and hands, but mucosal surfaces and the nail bed are also commonly involved4
  • In the hand and wrist region, cSCCs are most commonly found on the dorsum of the hand and the forearm, and only develop on the palms of the hand in rare circumstances4
  • Each case of conventional cSCC can be categorized into 1 of 3 histologic grades based its degree of nuclear atypia and keratinization:
    • Well differentiated: nuclei appear normal with abundant cytoplasm and extracellular keratin pearls
    • Moderately differentiated: features are an intermediary between well differentiated and poorly differentiated
    • Poorly differentiated: there is a high degree of nuclear atypia with frequent mitoses, a greater nuclear-cytoplasmic ratio, and less keratinization

Related Anatomy 

The nail united is comprised of the nail bed, nail folds, hyponychium and fingernail (nail plate).  The bed has two parts, the terminal matrix and the sterile matrix.  SCCNU involves the nail bed approximately 70% of the time.  SCCNU also occurs in the nail fold and rarely in both the fold and the nail bed.21

Incidence and Related Conditions

  • After basal cell carcinoma (BCC), cSCC is the second most common malignancy of the skin, but the most common subungual malignancy; it has an estimated annual incidence of 700,000 in the United States, which is a figure that appears to be rising5,6
  • The lifetime incidence of cSCC is between 7-11%, and it accounts for 20-25% of all non-melanoma skin cancers7,18
  • BCC and cSCC account for >95% of all non-melanoma skin cancers4
  • The incidence of cSCC is two times higher in men than women, and it increases markedly with age. About 80% of cases occur in people aged ≥60 years8
  • In the general population, <5% of cSCCs will metastasize to lymph nodes;11,12 however, in hospital-referred patients with unfavorable tumor characteristics, the incidence may be >10–15%13,14
  • Incidence of cSCC is 65–250 times higher among organ transplant recipients compared with the general population15

Incidence

SCCNU is rare.  High, et al found only 14 SCCNU's while doing 250,000 dermatology consults.20

Differential Diagnosis

  • AK
  • Allergic contact dermatitis
  • Atopic dermatitis
  • Atypical fibroxanthoma
  • BCC
  • Benign skin lesions
  • Bowen’s disease
  • Cancerous and pseudo-cancerous lesions
  • Chemical burns
  • Clear-cell acanthoma
  • Congenital tumors
  • Eccrine poroma
  • Hypertrophic lichen planus
  • Keratoacanthoma
  • Melanoma
  • Merkel cell carcinoma
  • Papillomas
  • Prurigo nodularis
  • Pyoderma gangrenosum
  • Pyogenic granuloma
  • Sebaceous neoplasms
  • Seborrheic keratosis
  • Sporotrichosis
  • Trichilemmoma
  • Vascular lesions
ICD-10 Codes

  • SKIN - MALIGNANT LESIONS: SQUAMOUS CELL CARCINOMA

    Diagnostic Guide Name

    SKIN - MALIGNANT LESIONS: SQUAMOUS CELL CARCINOMA

    ICD 10 Diagnosis, Single Code, Left Code, Right Code and Bilateral Code

    DIAGNOSISSINGLE CODE ONLYLEFTRIGHTBILATERAL (If Available)
    SQUAMOUS CELL CARCINOMA C44.629C44.622 

    ICD-10 Reference

    Reproduced from the International statistical classification of diseases and related health problems, 10th revision, Fifth edition, 2016. Geneva, World Health Organization, 2016 https://apps.who.int/iris/handle/10665/246208

Clinical Presentation Photos and Related Diagrams
Squamous Cell Carcinoma Clinical Photos
  • Squamous cell carcinoma (arrow) left hand at base of the fifth finger.
    Squamous cell carcinoma (arrow) left hand at base of the fifth finger.
  • Squamous cell carcinoma in a retired dentist who had been treated for months for a chronic "infection". While practicing dentistry, he had the habit of holding the X-ray film in his patient's mouth with his thumb as he shot the X-ray image.
    Squamous cell carcinoma in a retired dentist who had been treated for months for a chronic "infection". While practicing dentistry, he had the habit of holding the X-ray film in his patient's mouth with his thumb as he shot the X-ray image.
  • Squamous cell carcinoma (arrow) in a retired pediatrician who had been in the habit of holding his young patients while taking fluoroscopy images of their chest.
    Squamous cell carcinoma (arrow) in a retired pediatrician who had been in the habit of holding his young patients while taking fluoroscopy images of their chest.
Basic Science Photos and Related Diagrams
Squamous Cell Carcinoma Pathology
Basic Science Pics
  • Squamous cell carcinoma pathologic specimen
    Squamous cell carcinoma pathologic specimen
Symptoms
Persistent, thick, rough, scaly, red skin patch or non-healing ulcer
Change in pre-existing skin growth/development of new abnormal skin growth
Pain associated with a skin lesion
Loss of motor skills (with perineural invasion)
Paresthesia, anesthesia, and/or dysesthesia (with perineural invasion)
Typical History

The typical patient is a 67-year-old, fair-skinned male who lived in southern Florida his entire life. He spent much of his adolescence and early adulthood outdoors in the sun without wearing sunscreen, leaving his skin exposed to high quantities of solar UVR. Recently, he noticed an abnormally sized red skin growth on the dorsum of his right hand that was intermittently painful, leading him to consult with his doctor.  SCCNU are usually older males with a variety of nail complaints including infections under or around the nail, pain, a mass and/or ulceration.19

Positive Tests, Exams or Signs
Work-up Options
Images (X-Ray, MRI, etc.)
Squamous Cell Carcinoma Imaging
  • Squamous cell carcinoma X-ray right thumb with bone involvement (arrows).
    Squamous cell carcinoma X-ray right thumb with bone involvement (arrows).
  • Squamous cell carcinoma lateral X-ray of the thumb with bone involvement (arrow).
    Squamous cell carcinoma lateral X-ray of the thumb with bone involvement (arrow).
  • Squamous cell carcinoma AP X-ray of the thumb with bone involvement (arrow).
    Squamous cell carcinoma AP X-ray of the thumb with bone involvement (arrow).
Treatment Options
Treatment Goals
  • Identify cSCC tumors
  • Remove them completely
Conservative
  • Most cSCCs are low-risk, but surgery and other dermatological procedures are typically required to completely eradicate them; it is also essential to identify the significant proportion of cSCCs that are high-risk and make appropriate treatment decisions7
Operative
  • The goal is complete—preferably histologically confirmed—removal or destruction of the primary tumor and of any metastases, which requires identification of the margins of the tumor
  • Surgical excision
    • Regarded as the initial treatment of choice for most cases of cSCC; particularly indicated if the lesion is >2 cm wide or 4 mm deep, or in cases of perineural invasion or lymph node metastases2
    • Allows full characterization of the tumor and a guide to the adequacy of treatment through histological examination of the margins of the excised tissue2
    • May be combined with skin graft and/or radiation therapy
    • During the procedure, a margin of normal skin is excised from around the tumor
      • For clinically well-defined, low-risk tumors <2 cm in diameter, surgical excision with a minimum 4 mm margin around the tumor border is appropriate and would be expected to completely remove the primary tumor mass in 95% of cases; narrower margins of excision are more likely to leave residual tumor
      • Larger tumors, high-risk tumors, tumors extending into the subcutaneous tissue and those in high-risk locations should be removed with a wider margin (6 mm or more) and the tissue margins should be examined histologically, or with Mohs micrographic surgery2
    • Mohs micrographic surgery
      • Allows the precise definition and excision of a primary tumor growing in continuity, and may therefore reduce errors in primary treatment that may arise due to clinically invisible tumor extension; however, it does not identify in-transit micrometastases.  For this reason, some practitioners of this surgical intervention will excise a further surgical margin when treating high risk tumors after the Mohs surgical wound has been histologically confirmed to be clear of the primary tumor mass2
  • Radiation therapy
    • May be used alone or as an adjuvant intervention in some patients with high-risk cSCC, especially in cases where perineural invasion, positive (or indeterminate) surgical margins, or in-transit metastases are present2,16
  • Chemotherapy
    • May be used to increase survival in patients with high-risk or locally advanced cSCCs
    • Oral retinoids
      • Indicated for patients with multiple high-risk tumors
    • Oral capecitabine/oral 5-fluorouracil
    • Epidermal growth factor receptor (EGFR) inhibitors
      • EGFR is a receptor expressed in aggressive cSCCs
      • Gefitinib
      • Cetuximab16
  • Curettage and cautery
    • Destroys the tumor and a surrounding margin of clinically unaffected tissue with cauterization and scraping of the area with a curette
    • This process is repeated multiple times to maximize the probability of complete tumor extirpation
  • Cryosurgery:  May be an appropriate technique for certain cases, but is not appropriate for locally recurrent disease and caution should be exercised when using this intervention.2   Prior biopsy is necessary to establish the diagnosis histologically before proceeding with cryosurgery.
  •  
  • SCCNU requires excision.  Amputation is mandatory if the bone of the distal phalanx is invaded.33  Local excision or Mohs surgery can also be used.19,22
Treatment Photos and Diagrams
Squamous Cell Carcinoma Treatment
  • Plan for right thumb amputation for treatment of a subungual squamous cell carcinoma. Note pigment changes at arrow. Diagnosis made after an earlier nailed biopsy.
    Plan for right thumb amputation for treatment of a subungual squamous cell carcinoma. Note pigment changes at arrow. Diagnosis made after an earlier nailed biopsy.
  • Intra-operative right thumb amputation for treatment of a subungual squamous cell carcinoma.
    Intra-operative right thumb amputation for treatment of a subungual squamous cell carcinoma.
  • Post-operative X-ray of right thumb after amputation for treatment of a subungual squamous cell carcinoma.
    Post-operative X-ray of right thumb after amputation for treatment of a subungual squamous cell carcinoma.
  • Post-operative photo right thumb 4 months after amputation for treatment of a subungual squamous cell carcinoma.
    Post-operative photo right thumb 4 months after amputation for treatment of a subungual squamous cell carcinoma.
  • Post-operative photo right thumb 4 months after amputation for treatment of a subungual squamous cell carcinoma.
    Post-operative photo right thumb 4 months after amputation for treatment of a subungual squamous cell carcinoma.
Complications
  • Hematoma
  • Seroma
  • Infection
  • Wound dehiscence
Outcomes
  • Detection and treatment of cSCC at an early stage will increase the chances of achieving the best clinical outcome by minimizing the risk of spread and cSCC morbidity and mortality1
  • Most cases of cSCC treated surgically have an excellent prognosis, but 3.7-5.2% of patients experience nodal metastasis
    • The absolute number of cSCC patients who have nodal metastasis in the U.S. is estimated to be between 5,604-12,5725
    • The 5-year survival rate for cSCC after surgical excision is higher than 90%, and mortality is around 1%7
    • The absolute number of cSCC-related deaths is estimated between 3,932-8,791 annually5
  • Some of the most powerful independent predictors of nodal metastasis and death from cSCC are a tumor diameter of >2 cm, invasion beyond fat, poor differentiation, location on the ear or temple, and perineural invasion1
  • Rates of local recurrence and nodal metastases increase rapidly with higher numbers of cSCCs1
  • The incidence of local recurrent and metastatic disease after Mohs micrographic surgery are low, and it should therefore be considered in the surgical treatment of high-risk cSCC, particularly at difficult sites where wide surgical margins may be technically difficult to achieve without functional impairment; Mohs micrographic surgery is also becoming increasingly popular and has high cure rates2
  • Small doses of oral retinoids have been found to reduce the number of cSCCs and recurrence in immunosuppressed patients, while oral capecitabine or its active form, oral 5-fluorouracil, have been shown to effectively treat locally advanced cSCCs16
  • Gefitinib has been shown to increase survival in patients with cSCC in some trials, while cetuximab has yielded positive results both alone and in combination with 5-fluorouracil and cisplatin, and has been shown to improve prognosis in patients with locally advanced cSCC, both with and without radiation therapy16
  • Excellent cure rates have been reported in the removal of small (<1 cm) well-differentiated, primary, slow-growing tumors arising on sun-exposed sites with curettage2
  • Good short-term cure rates have been reported for small histologically confirmed cSCCs treated by cryosurgery2
  • Incomplete surgical excision is associated with a worse prognosis; therefore, when doubt exists as to the adequacy of excision after surgery, it is best to delay or modify wound repair until complete tumor removal has been confirmed histologically2
  • Recurrence of SCCNU is rare after amputation or complete excision but does occur after local excision.19
Key Educational Points
  • There is a lack of randomized controlled trials on the treatment of primary cSCC, and there is widely varying malignant behavior in the tumors that fall within this histological diagnostic category2
  • Clinicians and pathologists must work closely together to ensure appropriate sampling and microscopic examination of excised tissue, particularly with high-risk cSCC tumors
  • Since most patients with cSCC will not develop nodal metastases, the elective treatment of lymph nodes for all patients is considered inappropriate
    • Accurately predicting patients that are at high risk and therefore justifying the elective treatment of first echelon lymph nodes is difficult; however, patients with more than one high-risk factor (deeply invasive >4–5 mm, >2 cm in diameter), especially in the recurrent setting, should be considered at risk of developing nodal metastases, and elective treatment to first echelon nodes may be beneficial17
  • The histology report should include the pathological pattern, cell morphology, degree of differentiation, histological grade, depth, level of dermal invasion, and the presence or absence of perineural, vascular, or lymphatic invasion (Motley)
  • Since 95% of local recurrences and 95% of metastases are detected within five years, patients with a high-risk cSCC should be kept under observation for recurrent disease for this period of time and be instructed to follow self-examination techniques2
  • When dealing with a potential SCCNU, the surgeon will do well to remember that cancer can look like an infection and infection can looks like cancer.  Therefore, when biopsying these lesions, one should also culture them and visa versa.
References

Cited

  1. Green AC, Olsen CM. Cutaneous squamous cell carcinoma: an epidemiological review. Br J Dermatol 2017. PMID: 28211039
  2. Motley R, Kersey P, Lawrence C, et al. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Plast Surg 2003;56(2):85-91. PMID: 12791348
  3. Schmitt J, Seidler A, Diepgen TL, Bauer A. Occupational ultraviolet light exposure increases the risk for the development of cutaneous squamous cell carcinoma: a systematic review and meta-analysis. Br J Dermatol 2011;164(2):291-307. PMID: 21054335
  4. Yanofsky VR, Mercer SE, Phelps RG. Histopathological variants of cutaneous squamous cell carcinoma: a review. J Skin Cancer 2011;2011:210813. PMID: 21234325
  5. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 2013; 68(6):957–966. PMID: 23375456
  6. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010; 146(3):283–287. PMID: 20231499
  7. Martorell-Calatayud A, Sanmartín Jimenez O, Cruz Mojarrieta J, Guillén Barona C. Cutaneous squamous cell carcinoma: defining the high-risk variant. Actas Dermosifiliogr 2013;104(5):367-79. PMID: 23683506
  8. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet 2010; 375:673–85. PMID: 20171403
  9. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol 2006; 16:335–9. PMID: 1693578
  10. Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol 2013; 169:502–18. PMID: 23647091
  11. Nixon RL, Dorevitch AP, Marks R. Squamous cell carcinoma of the skin. Accuracy of clinical diagnosis and outcome of follow-up in Australia. Med J Aust 1986; 144: 235–9. PMID: 3587093
  12. Czarnecki D, Staples M, Mar A, et al. Metastases from squamous cell carcinoma of the skin in southern Australia. Dermatology 1994; 189: 52–4. PMID: 8003787
  13. Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 2002; 28: 268–73. PMID: 11896781
  14. Afzelius LE, Gunnarsson M, Nordgren H. Guidelines for prophylactic radical lymph node dissection in cases of carcinoma of the external ear. Head Neck Surg 1990; 2: 361–5. PMID: 7364589
  15. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999; 18:2693–708. PMID: 10521860
  16. Nuño-González A, Vicente-Martín FJ, Pinedo-Moraleda F, López-Estebaranz JL. High-risk cutaneous squamous cell carcinoma. Actas Dermosifiliogr 2012;103(7):567-78. PMID: 22261673
  17. Veness MJ. Treatment recommendations in patients diagnosed with high-risk cutaneous squamous cell carcinoma. Australas Radiol 2005;49(5):365-76. PMID: 16174174
  18. Ilyas EN, Leinberry CF< Ilyas AM.  Skin cancers of the hand and upper extremity.  J Hand Surg 2012; 37A:171-178.
  19. Dijksterhuis A, Friedeman E, van der Heijden B.  Squamous cell carcinoma of the nail unit: review of the literature.  J Hand Surg Am 2018; 43(4):374-379
  20. High WA, Tyring SK, Taylor RS.  Rapidly enlarging growth of the proximal nail fold.  Dermatol Surg. 2003;29(9):984-986.
  21. Doyle R.  Amputations.  In: Hand and Wrist.  Chapter 14.  Philadelphia: Lippincott Williams & Wilkins; 2006:226-227.
  22. Peterson SR, Layton EG, Joseph AK.  Squamous cell carcinoma of the nail unit with evidence of bony involvement: a multidisciplinary approach to resection and reconstruction.  Dermatol Surg. 2004:30 (2 Pt 1):218-221.
  23. Carroll Re> Squamous cell cardinoma of the nail bed.  J Hand Surg Am. 1976;1(2):92-97.

New Articles

  1. Green AC, Olsen CM. Cutaneous squamous cell carcinoma: an epidemiological review. Br J Dermatol 2017. PMID: 28211039

Reviews

  1. Green AC, Olsen CM. Cutaneous squamous cell carcinoma: an epidemiological review. Br J Dermatol 2017. PMID: 28211039
  2. Schmitt J, Seidler A, Diepgen TL, Bauer A. Occupational ultraviolet light exposure increases the risk for the development of cutaneous squamous cell carcinoma: a systematic review and meta-analysis. Br J Dermatol 2011;164(2):291-307. PMID: 21054335
  3. Yanofsky VR, Mercer SE, Phelps RG. Histopathological variants of cutaneous squamous cell carcinoma: a review. J Skin Cancer 2011;2011:210813. PMID: 21234325
  4. Nuño-González A, Vicente-Martín FJ, Pinedo-Moraleda F, López-Estebaranz JL. High-risk cutaneous squamous cell carcinoma. Actas Dermosifiliogr 2012;103(7):567-78. PMID: 22261673
  5. Veness MJ. Treatment recommendations in patients diagnosed with high-risk cutaneous squamous cell carcinoma. Australas Radiol 2005;49(5):365-76. PMID: 16174174
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