Cancer, Skin (Integument)


Article Author:
Paul Gruber
Muneeb Shah


Article Editor:
Patrick Zito


Editors In Chief:
Myron Bodman
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
6/23/2019 12:46:20 PM

Introduction

Skin cancer is the most common form of cancer in the United States. Skin cancer is generally classified as nonmelanoma skin cancer (NMSC) or melanoma. The exact incidence of skin cancer is difficult to determine due to the lack of diagnostic criteria and underreporting. However, several epidemiologic studies have shown an increasing incidence of both NMSC and melanoma over the past several decades.[1][2] The diagnosis and treatment of these neoplasms represent a significant health problem from the standpoint of patient well-being and healthcare expenditures. Skin cancers are frequently located on the sun-exposed head and neck regions, which can result in significant morbidity during their diagnosis and treatment. Treatment options including surgical excision, cryotherapy, chemotherapy, immunotherapy, and radiation. Proper sun safety (i.e., sunscreen) is of the utmost importance to prevent skin cancer.

Etiology

Ultraviolet (UV) solar radiation is the major etiologic factor in the development of cutaneous malignancies. An overwhelming majority of cases of NMSC and melanoma are related to UV exposure.[3][4] UV exposure induces carcinogenesis by a twofold mechanism; it generates DNA damage that leads to mutation formation and reduces the ability of the host immune system to recognize and remove malignant cells. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common forms of NMSC and both are derived from mutated epidermal keratinocytes. The cumulative lifetime UV exposure is directly correlated with risk for developing BCC and SCC. Melanoma is the deadliest form of skin and is derived from mutated melanocytes. In contrast to BCC and SCC, the risk of developing melanoma is directly correlated with sun exposure during adolescence, specifically the number of sunburns from age 15-20.[5] Other risk factors implicated in the development of cutaneous malignancies include family history, chemical exposure, tanning bed use, human papillomavirus (HPV), Fitzpatrick skin type, the presence of melanocytic nevi, and immunosuppressed status.[6]

Epidemiology

There are more skin cancers in the United States population than all other cancers combined.[7] These cancers are on the rise, representing a significant health problem from the standpoint of patient well-being and health expenditures.[8] Skin cancer occurs in all races worldwide, however, the risk is substantially higher in Caucasians due to the photoprotective effects of epidermal melanin.[9] In individuals with fair skin, approximately 75% to 80% of non-melanoma skin cancers are basal cell carcinomas, and up to 25% are squamous cell carcinomas. Heritable defects in DNA repair mechanisms, as seen in xeroderma pigmentosum and Muir-Torre Syndrome, also make afflicted individuals at high risk for cutaneous carcinomas. 

Pathophysiology

Sun exposure is the most important modifiable risk factor associated with the development of NMSC and melanoma. UV radiation can be subdivided into UV-A, UV-B, and UV-C. Sunlight is primarily composed of the UV-A (~90%) and UV-B (~10%) components.[3] UV-C rays are mostly absorbed by the atmosphere. UV-A has a longer wavelength (320-400 nm) and penetrates into the dermis causing the formation of free radicals. UV-B has a shorter wavelength (290-320 nm), penetrates to the level of the stratum basale of the epidermis, and causes the formation of thymine dimers. Both UV-A and UV-B contribute to carcinogenesis, however, UV-A is thought to play a larger role. UV radiation causes cell injury, apoptosis, and impairs DNA repair mechanisms leading to DNA mutations. 

The development of cutaneous malignancy after DNA damage by solar radiation is multifactorial, including genetic factors, Fitzpatrick skin type, and immunosuppressed status. A majority (90%) of cutaneous squamous cell carcinoma have UV-induced P53 gene mutations leading to the uninhibited proliferation of keratinocytes.[10] DNA mutations implicated in basal cell carcinoma include mutations in the PTCH gene and the p53 gene.[11] DNA mutations implicated in melanoma include mutations in cyclin-dependent kinase Inhibitor 2A (CDKN2A), melanocortin receptor 1 (MCR1), B-Raf, and DNA repair enzymes (e.g., UV-specific endonuclease in xeroderma pigmentosum).[12][13]

History and Physical

Thorough skin examination is useful to identify premalignant and malignant skin lesions. It is important to note location, texture, size, color, shape, borders, and any recent change of suspicious lesions. Premalignant actinic keratoses often present as rough, gritty skin papules on an erythematous base. Basal cell carcinomas usually appear as pink pearly papules with telangiectasias. Squamous cell carcinomas are often pink, rough papules, patches, and plaques. Melanomas are characteristically brown-to-black lesions with asymmetry, irregular borders, color variegation, and diameters greater than 6 mm. Any new/changing lesion or lesion that appears different than other nevi on the body ("ugly duckling sign") is considered suspicious.[14]

Basal cell carcinomas and squamous cell carcinomas are commonly noted on parts of the head and neck which receive the most cumulative UV  radiation over the course of a lifetime, such as a nose, ear, and upper lip. Melanomas can occur anywhere on the body and are most frequently discovered on the backs and shoulders of men and the lower limbs of women.[15] However, studies comparing the risk of melanoma per unit area of skin have found the face to be the highest risk area for melanoma.[16]  

Evaluation

Evaluation of patients at risk for cutaneous carcinoma usually includes a full body skin examination by a medical professional. This can be done by most primary care providers; however, the evaluation often is performed by specialists with three years of post-medical school advanced dermatology training. The vast majority of concerning lesions on physical examination will undergo an office procedure called a skin biopsy. This is done under local anesthesia during an outpatient office visit. The specimen is then sent for special interpretation by a trained dermatopathologist. If the pathologist reading the tissue specimen under the microscope confirms the diagnosis of cutaneous malignancy, further intervention is usually warranted based upon the pathologic diagnosis and clinical scenario.

Treatment / Management

Treatment of precancerous lesions and cutaneous carcinoma should be tailored toward the individual patient scenario and the best clinical outcome. If presenting as isolated lesions, precancerous actinic keratoses can be treated with lesion-directed therapies such as cryotherapy.[17] Often patients may present with numerous lesions and diffuse actinic damage, which require field-directed therapy as opposed to individually treating each lesion.[17]  This can be done with topical agents (5-fluorouracil, imiquimod, and ingenol mebutate) or with photodynamic therapy after sensitizing the skin with a topical agent. Initial pre-emptive efforts should be made to reduce the patient's risk profile for developing cutaneous carcinoma including optimizing the immunosuppressant regimen in solid organ transplant patients, proper surveillance schedules in patients treated with immunomodulatory therapies, and adequate therapy of precancerous lesions. 

Basal cell carcinomas and squamous cell carcinomas, if superficial, can be treated with topical therapies depending on provider preference. However, the standard practice is to surgically treat these lesions with destructive means such as electrodesiccation and curettage or surgical excision. Skin cancers greater than 2 cm in diameter and those located on functionally and cosmetically sensitive sites (head/neck, hands, and feet, genitalia) usually are referred for a special surgical procedure called Mohs micrographic surgery.[18] Some patients with aggressive and recurrent forms of basal cell carcinoma who are not good surgical candidates are treated with radiation therapy or systemic medications (e.g., vismodegib for basal cell carcinoma).[19] 

Melanoma is the most aggressive and lethal form of cancer and the gold standard of treatment is surgical excision. If caught early, surgical excision can be curative. Later stage tumors portend a poor prognosis and often require adjuvant chemotherapy or immunotherapy.[20]

Enhancing Healthcare Team Outcomes

Skin cancers are frequently encountered in clinical practice by the primary care provider, nurse practitioner, and the internist. In all cases, the patient should be referred to a dermatologist for final confirmation. While the treatment of skin cancer is done by an oncologist and a dermatologist, the primary care providers play a vital role in prevention. Patients should be educated about avoiding too much sun, wearing appropriate garments when going outdoors, and applying sunscreen. Finally, patients should be educated on how to inspect their skin and when to seek medical assistance. [21]


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Cancer, Skin (Integument) - Questions

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What is the most common malignancy in post-transplant patients?



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A 64-year-old farmer presents with a 1-month history of enlarging skin lesion on his face. He denies any recent injury. He has a history of diabetes mellitus, well-controlled with metformin. Vital signs are within normal limits. Physical examination reveals a 2-cm pearly lesion on the upper lip. The lesion is not tender to palpation. The practitioner is concerned that the lesion could be cancerous and recommends a biopsy. A biopsy is most likely to reveal which of the following?



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A 65-year-old woman comes to the physician because of a 9-mm papule that has changed considerably in size and color over the past couple of months. There is no personal or family history of skin cancer. Physical examination reveals a flat, heterogeneous, brown-to-black lesion with irregular borders on the dorsum of the hand. Which of the following would be the most appropriate next step in management for this patient?



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A 68-year-old white man comes to the physician for a follow-up examination. He has no complaints. He has smoked 1 pack of cigarettes daily for the past 30 years. Also, his last colonoscopy was 8 years ago. The vital signs today are within normal limits. Physical examination is unremarkable. He is at the highest risk for developing which of the following forms of cancer?



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A 68-year-old woman comes to the physician because of palpable lymph nodes in the left axilla. She denies weight loss, and her vital signs are within normal limits. Mammography is negative for breast malignancy. A biopsy is performed on the left axillary lymph nodes. Histopathology shows a malignancy with multiple sites with pyrimidine cross-linking forming pyrimidine dimers. Which of the following is the most likely site of origin of this cancer?



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A 32-year-old woman comes to her primary care physician for a wellness examination. She reports a family history of cancer and is concerned about her risk of developing cancer. After discussing primary prevention measures, the physician recommends a healthy diet, exercise, daily sunscreen use, and a pap smear. This woman is at risk of developing which of following cancer in the future?



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Cancer, Skin (Integument) - References

References

Skin Cancer Prevention (PDQ®): Health Professional Version 2002;     [PubMed]
Rogers HW,Weinstock MA,Feldman SR,Coldiron BM, Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA dermatology. 2015 Oct;     [PubMed]
Glazer AM,Winkelmann RR,Farberg AS,Rigel DS, Analysis of Trends in US Melanoma Incidence and Mortality. JAMA dermatology. 2017 Feb 1;     [PubMed]
D'Orazio J,Jarrett S,Amaro-Ortiz A,Scott T, UV radiation and the skin. International journal of molecular sciences. 2013 Jun 7     [PubMed]
Armstrong BK,Kricker A, How much melanoma is caused by sun exposure? Melanoma research. 1993 Dec     [PubMed]
Wu S,Han J,Laden F,Qureshi AA, Long-term ultraviolet flux, other potential risk factors, and skin cancer risk: a cohort study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2014 Jun     [PubMed]
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