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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 2  |  Page : 407-412

A comprehensive review on basal cell carcinoma of the head-and-neck region


Department of Oral Pathology and Microbiology, Sharad Pawar Dental College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Sawangi (M), Wardha, Maharashtra, India

Date of Submission24-Sep-2019
Date of Decision08-Nov-2020
Date of Acceptance08-Jan-2021
Date of Web Publication18-Oct-2021

Correspondence Address:
Dr. Rajul Ranka
Desh Sewa Road, Jain Mandir Ward, Hinganghat, Wardha, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdmimsu.jdmimsu_143_19

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  Abstract 


Basal cell carcinoma (BCC) is an exceedingly common cutaneous malignancy. Its frequency is rising worldwide by up to 10% a year. Even though mortality is very low as BCC hardly ever undergoes metastasis, this malignancy is highly devastating, has high morbidity rate, and is troublesome for healthcare services worldwide. Furthermore, people who have this condition are at high risk of developing further BCC and other malignancies such as squamous cell carcinoma and malignant melanoma. This review aims to present a comprehensive overview of this pivotal condition, concentrating on recent advances in our understanding of its epidemiology, risk factors, molecular genetics, diagnosis, and treatment in Southeast Asia.

Keywords: Basal cell carcinoma, basal cell nevus syndrome, rodent ulcer, skin cancer


How to cite this article:
Ranka R, Sharma P. A comprehensive review on basal cell carcinoma of the head-and-neck region. J Datta Meghe Inst Med Sci Univ 2021;16:407-12

How to cite this URL:
Ranka R, Sharma P. A comprehensive review on basal cell carcinoma of the head-and-neck region. J Datta Meghe Inst Med Sci Univ [serial online] 2021 [cited 2021 Dec 9];16:407-12. Available from: http://www.journaldmims.com/text.asp?2021/16/2/407/328448




  Introduction Top


Basal cell carcinoma (BCC) is an exceedingly common cutaneous malignancy, with increasing annual occurrence throughout the world. Jacob Arthurin in 1827 first coined the term “rodent ulcer” to describe BCC.[1] It is a slothful primary neoplasm of the skin arising from the basal cell layer of the epidermis. It is locally aggressive, can cause destruction of adjacent structures, and is capable of invading skin, which may involve the deeper tissues, such as muscles, cartilage, bones, and vital structures, but its metastatic potential is low (0.0028%–0.55%).[2],[3] When confined to the scalp, the massive BCC is capable of invading the periosteum, the bone, the dura mater, and the brain, making it a lethal condition. Advanced BCC may cause severe disfigurement and morbidity, leading to deprived life. The individual who suffers are at greater risk of developing multiple BCC and other malignancies.[4] BCCs of the head-and-neck region are seen in 85% of cases and are extremely serious as they impede the esthetics, leading to poor and depressing social life for patients. This review aims to comprehensively describe this devastating disease, highlighting on recent advances in our understanding of its epidemiology, risk factors, pathophysiology and molecular genetics, clinical characteristics, histopathology, imaging, recurrence and metastasis, and treatment and prognosis in Southeast Asia.


  Epidemiology Top


The incidence of BCC has increased since the mid-2000s, but the estimates of the incidence are imprecise since there is no cancer registry that collects data on BCC.[5] The incidence of BCC has discernible geographical variation. In Asian patients, the reported incidence of BCC ranges from 16 to 20 per 100,000 but has been shown to be on the rise since the 1960s.[6] Taking into account the increasing incidence rate of this tumor by 3%–10% per year, it has become an ever-growing public health problem.[7]

Although BCC can occur at any age, its incidence increases markedly after the age of 40.[8] It most frequently occurs in elderly white-skinned people in the seventh to eighth decades of life, but it is more aggressive in the age group below 35 years. Sporadic BCC is usually not seen before the age of 20 years. Childhood onset of BCC is rare and is usually associated with genetic disorders, while idiopathic childhood onset is uncommon.[9] Individuals with a history of BCC are at higher risk for successive lesions, and approximately 40% of patients who have had one BCC will develop another lesion within a span of 5 years.[10] BCC generally affects men and is rare in dark-skinned races. It is interesting to note that among the studies of Asians, the male-to-female ratio is about one and Indian studies reported female predominance of BCC.[6],[11] These differences could be due to varied pattern of sun exposure in different regions.


  Common Risk Factors Top


The most significant risk factors are fair skin and exposure to ultraviolet (UV) radiation. In the head-and-neck region, partially upper face areas show more incidences because of sun exposure. Besides cutaneous phototype and exposure to UV radiation, various other risk factors are exposure to photosensitizing drugs and ionizing radiation; environmental carcinogens, e.g., arsenic, alkylating agents, polycyclic aromatic hydrocarbons; repeated cutaneous trauma; scars; male gender; elder age; high dietary energy, especially fat, and low intake of vitamins; and immunosuppression.[12],[13],[14] In immunocompromised patients, BCCs appear on the nonexposed skin of the body and upper limbs.[15] A study reports a strong association between excessive alcohol drinking and higher incidence of sunburn, indicating a link between alcohol consumption and skin cancer.[16] BCC is also associated with certain genetic disorders and syndromes, the most common of which is basal cell nevus syndrome (BCNS, Gorlin Goltz syndrome) which often involves oral and head-and-neck region and should be recognized by dentists. Other disorders include xeroderma pigmentosum, epidermodysplasia verruciformis, nevus sebaceous, albinism, Gardner's syndrome, Bazex's syndrome or Rombo syndrome, a familial history of skin cancer, or DNA repair deficiencies, leading to chromosomal instability.[12],[17]

The meticulous relationship between risk of BCC and the amount, timing, and pattern of UV exposure remains unclear. The risk correlates with the amount and the nature of accumulated exposure, especially during childhood. A latency period of 20–50 years is quintessential between the time of UV damage and clinical onset of BCC. Both ultraviolet B (UVB) radiation and ultraviolet A (UVA) radiation contribute to the formation of BCC, among which UVB plays a greater role.[18] UVB irradiation directly damages cellular DNA and RNA causing covalent bonding between adjacent pyrimidines and formation of mutagenic products. UVA produces the formation of toxic reactive oxygen species. In a 2012 systematic review and meta-analysis, Wehner et al. found that indoor tanning was associated with a significantly increased risk of BCC.[19] Boyd et al. found that BCC in young women is linked with past or current smoking.[20] Skin type is associated with melanocortin 1 receptor (MC1R) polymorphisms and is an independent risk factor for BCC.[21]


  Pathophysiology and Molecular Genetics Top


BCC comprise multifactorial etiology; the combination of genotype, phenotype, and environmental factors is involved in its development. Exposure to UV radiation is the main causative factor in the pathogenesis of BCC, yet the magnitude of the risk associated with increased exposure is inadequate to elucidate either why certain populations get these tumors while others do not, or the substantial phenotypic diversity shown by patients in terms of the number and site of tumor and patterns of presentation.[22] The amount of damage caused by UV exposure is associated with the pigmentation within the skin. The clinically observed pigmentation within the skin is unrelated to either epidermal thickness or the number of melanocytes. Moreover, it is related to the size, density, and distribution of melanosomes in keratinocytes.[23] The Asians have small, dense melanosomes, usually clustered within membrane-bound organelles.[6] Matsuoka et al. demonstrated that an increase in skin pigmentation causes reduced penetration of photons into the deeper layers of the epidermis. Hence, there is reduced UVB-stimulated Vitamin D3 synthesis in Asians.[24]

Susceptibility to BCC seems to be determined by a complex interaction between duration and intensity of exposure to UV radiation and polymorphic genes. Genes associated with susceptibility are cytochrome (CYP) 450 and glutathione S-transferase (GST), both involved in detoxifying various mutagens. Specific polymorphisms within these supergenes have been identified, in particular GSTM1, GSTT1, GSTP1, and CYP2D6. Multiple BCCs might be associated with CYP2D6.[21],[25]

BCNS is due to mutation in the patched (PTCH) gene located on chromosome 9q22. Sporadic BCCs also display frequent loss of heterozygosity at 9q22, with inactivating PTCH mutations (68% of cases).[26] BCCs were essentially a molecular “black box” until the identification of a genetic flaw in a rare subset of patients who had a great propensity to develop BCCs pointed to aberrant Hedgehog signaling as the prime defect, leading to the formation of these tumors.[27] Patched 1 protein (PTCH1) and smoothened protein (SMO) are integrants of the receptor complex for the sonic Hedgehog protein that directs embryonic development of various organs. PTCH is the human homolog of the Drosophilia PTCH gene; it negatively regulates Hedgehog signaling pathway via the inhibition of SMO, a transmembrane protein. Inactivating mutations of PTCH in BCNS stimulate aberrant Hedgehog signaling and subsequent BCC development.[28] Mutations in tumor suppressor gene p53 cause inactivation of the gene and development of tumors resistant to apoptosis. Mutations in p53 and MC1R genes may cause development of BCCs; about 53% of BCCs show single allele p53 mutation.[29],[30]


  Diagnosis Top


Clinical features

BCCs present varied subtypes and occur at different anatomical locations. Approximately 70%–80% of BCCs occur on the head-and-neck commonly involving nose and eyelids.[2] The reported cases of head-and-neck region presented scalp involvement; skull bone destruction, orbit, eyelid, lacrimal apparatus, and ocular globe involvement; and antrum, hard palate, and mandible involvement.[31] All these cases presented with destructive and massive BCCs as they were result of negligence mainly.

BCC may be subdivided into nodular (60%) or superficial (30%) on clinicopathologic grounds, the less common subtypes being sclerodermiform (morpheaform or morphoeic), cystic, infiltrative, micronodular, pigmented, and fibroepithelioma of Pinkus.[15],[32]

The classic form of BCC is the rodent ulcer, which has an ulcerated center and an indurated edge. Early BCCs present as a small translucent or pearly papule with a telangiectatic vessel within it. The other patterns of BCC include nodular or cystic, superficial, morphoeic, and pigmented. Nodular and cystic BCCs show moreover well-defined borders, while micronodular, morphoeic, infiltrative, trabecular, and basosquamous BCCs show often less well-defined borders but are more aggressive.[33]

Superficial BCC is particularly slow growing, presents as scaly macules or thin well-demarcated erythematous plaques, and may be amenable to topical treatments as a result of their minimal depth of invasion.[12] Nodulocystic or nodular BCC presents as a solitary, exophytic, pearly, red nodule with large telangiectatic vessels. The endophytic nodules appear as flat enduring plaques. Nodular BCC accounts for 60%–80% and is most commonly found on the head.[34] The most significant clinical subtype of BCC is the morphoeic form. These are highly aggressive, presented as infiltrated plaque with slightly shining surface and ill-defined borders, often presented late, and are difficult to diagnose.[35] Clinically micronodular BCC are elevated or flat infiltrated tumors. They seldom ulcerate and have yellow-whitish color when they are flat, ostensibly clear outlines, and thick at palpation. Fibroepithelioma of Pinkus usually originates as elevated pink or erythematous nodules. The lesions are solitary and affect especially women. Pigmented BCC accounts for only 6% of cases, consists of dark-brown or black melanin pigmentation, and presents as a well-defined papule or nodule over sun-exposed areas. It is slow-growing, locally invasive and rarely metastasizes. Linear BCC is a distinct clinical entity, is aggressive, and shows increase in subclinical extension.[36]


  Differential Diagnosis Top


Differential diagnoses of BCC include squamous cell carcinoma (fibroepithelioma of Pinkus), Bowen's disease (superficial BCC), psoriasis (superficial BCC), discoid eczema (superficial BCC), malignant melanoma (pigmented BCC), melanocytic nevi (pigmented BCC), keratosis, keratoacanthoma, seborrheic keratosis (pigmented BCC, fibroepithelioma of Pinkus), subtle scar-like plaque (morphoeic BCC), sebaceous hyperplasia, molluscum contagiosum, and appendageal tumors.[15],[34],[35]


  Histopathology Top


Skin biopsy is performed in the majority of cases to aid diagnosis and identify subtype of BCC for treatment planning. BCC is an epithelial malignant tumor comprising cells which look-like the basal epidermis layer (basaloid cells). All types of BCC depict certain typical diagnostic histological features. In particular, all have basaloid cells with thin scanty pale eosinophilic cytoplasm surrounding round-to-oval nuclei comprising rough granular chromatin pattern. The peripheral borderline cell layers are characterized palisading arrangement of nuclei or picket-fence pattern, and the surrounding stroma is often separated by slits. Almost all tumors originate in the epidermis and invade the dermis in the form of solid or cystic nodules or streaky projections creating various growth patterns. Intercellular bridges may be present. Mitoses may be rare or multiple. Central necrosis is often seen in greater tumor nodules.[37]

The basic histological subtypes of BCC formed up to 90% of all histological types and reported in published literature are nodular (solid), superficial (multicentric, multifocal), and infiltrative. Nodular type presents with nest-like infiltration from basaloid cells, with a typical peripheral palisading of the cells. It shows cystic variant, adenoid variant, and fibroepithelial variant based on histological patterns.[38] Superficial type depicts nests of the basaloid cells located subepidermally and no infiltration of tumor cells in the reticular dermis. The nests are often surrounded by thin strands of fibrous stroma with lymphocyte infiltrate and thin-walled blood vessels.[39] Infiltrative type shows thin, nest-like bundles of the basaloid cells infiltrating in the dermal collagenous fibers. It has two variants: sclerosing and nonsclerosing. The sclerosing variant can be fibrosing, morphoeic, cicatricial, or desmoplastic and characteristically show abundant fibroblasts and the presence of desmoplastic stroma, which gives tumor a characteristic clinical picture of a keloid scar.[40] Another type is pigmented BCC in which the pigment is present in the basal keratinocytes with marked increase in melanocytes.


  Imaging Top


The role of imaging in the evaluation of BCC is evolving. Imaging is indicated if there is the presence of extensive disease, suspected T3 or T4 tumors, or metastatic disease. Computed tomography (CT) or magnetic resonance imaging is performed for bony, vascular, or major nerve invasion. Dermatoscopy may be helpful to identify arborizing blood vessels, ulceration, maple leaf-like areas, characteristic of BCC. High-frequency ultrasound (15–22 MHz) has a promising role in the evaluation of primary BCC. CT and positron emission tomography/CT both are widely used for assessing baseline metastatic disease and response to treatment.[40]


  Recurrence and Metastasis Top


Recurrence

Approximately 40% of patients with BCC have a recurrent skin lesion within 5 years, and the rate is even more in histopathologically advanced cases.[41] Patients with BCC have an increased risk of developing subsequent BCC. In a recent meta-analysis, the 3-year cumulative risk varied between 33% and 77% and the risk seems to depend on the number of lesions present. The risk of developing squamous cell carcinoma and melanoma is also tremendously high after first BCC.

Metastasis

The incidence of metastasis has been estimated to be 0.003%–0.55% in various studies. BCC can spread via lymphatics or hematogeneously. A recent meta-analysis of metastatic BCC revealed regional metastasis to adjacent nodes, skin, and subcutaneous tissue, salivary glands, or muscles. After metastatic adenopathy (54%), the lungs (28%), bones (24%), skin (11%), salivary glands (7%), and liver (4%) were the most commonly affected organs. Large lesions invading deep structures, lesions exhibiting perineural invasion, lesions with aggressive histopathologic features, and long-standing lesions are capable of metastasis.[3],[42]


  Management Top


Surgical excision

BCC is excised usually with the clearance of 3–4 mm of normal skin margin to ensure the complete excision of lesion. The excised tissue is fixed in formalin and is subjected to histopathological processing and staining. The standard surgical excision sometimes accompanies with complications and has 10.1% recurrence rate at 5-year follow-up.[43]

Mohs micrographic surgery

Mohs surgery is often used for extensive and destructive lesions located on the face and recurrent BCC. It has high cure rates (5-year cure rate for primary BCC and for recurrent BCC is 99% and 94.4%, respectively). There is maximal preservation of normal tissue, and henceforth, this procedure is the treatment of choice for high-risk BCCs. The disadvantages of this method are that it requires special laboratory facilities, trained personnel, and also long duration of procedure. Therefore, it should be considered whenever there is a need for maximal tissue preservation and in cases of recurrences after surgery or radiotherapy (RT), high-risk anatomical sites, and large tumors.[44]

Cryosurgery

Cryosurgery involves the destruction of tissue using liquid nitrogen. Cryosurgery is often used in the treatment of low-risk BCCs although fair results are reported in the treatment of high-risk lesions, either as sole treatment or in combination with curettage. Cryosurgery is not first line of treatment for facial BCCs due to the high risk of recurrence and potentially poorer cosmetic outcome compared to surgical treatment modalities.[45]

Curettage and cautery

Curettage and cautery is a regularly used treatment modality by dermatologists in the management of BCC. The tumor is scraped with a curette and then treated with electrocautery to control bleeding and destroy any cancer cells at the base and margin of the wound. The cycle is repeated once or twice for increased efficacy. A study has reported a 5-year cumulative recurrence rate of 6%–19%. Recurrence was higher for central facial areas.[46]

Roentgen therapy

Roentgen therapy or RT is an efficacious treatment modality for primary BCCs, recurrent BCCs when surgery is not an option, as adjuvant therapy, in old age patients due to their comorbidity or when surgery is contraindicated, large size of the tumor or inaccessible lesions. Head-and-neck area generally tolerates RT well. It should be avoided in morphoeic BCC as it is radioresistant and superficial BCC due to poor cosmetic result. The treatment regimen and dose mainly depend on size of the tumor, its location, type, and depth. Primary BCCs irradiated by a “standardized” X-ray therapy schedule have a 5-year recurrence rate of 7.4%–9.5%. RT is contraindicated in genetic disorders which predispose patients to skin cancers, patients with connective tissue diseases, as well as patients who have recurrent BCC after previous RT.[43]


  Management of Metastatic Basal Cell Carcinoma Top


Systemic chemotherapy is the mainstay of treatment of metastatic BCC. Both targeted therapies for inhibition of the Hedgehog signaling pathway and conventional chemotherapy are used. Vismodegib and sonidegib are orally administered small molecule inhibitor of SMO, approved by the Food and Drug Administration for the treatment of metastatic and recurrent locally advanced BCC. The drugs are strictly contraindicated in pregnancy. Platinum-based chemotherapy is the most commonly used conventional chemotherapy regimen for BCC.[40],[47]

Various other treatment modalities for BCC include use of laser ablation, tropical 5% imiquimod cream (Aldara), tazarotene, photodynamic therapy, topical 5-fluorouracil 5% (Efudex), intralesional interferon alpha, solasodine glycoalkaloids, and ingenol mebutate. These modalities also have good potential in treating BCCs and newer regimens are emerging.


  Follow-up and Prognosis Top


Clinical follow-up at 6–12-month intervals is recommended for life after the treatment of localized BCC, for detecting recurrent disease and new lesions.[29] However, given that patients are at risk of developing further BCC and other cutaneous and noncutaneous malignancies, it should be prudent to follow-up high-risk patients with multiple lesions. The prognosis for most patients with BCC is excellent as metastasis is rare. Education on sun avoidance and tumor detection may help prevent further malignancies and facilitate diagnosis of smaller BCCs, which, in general, are easier to treat and have less morbidity.


  Conclusion Top


BCC is still a disease of concern because of its negligence by patients and poor esthetics. A timely diagnosis and early treatment may lead to better prognosis of patients. Hence, the spread of awareness about this disease has a prophylactic importance. Recent research has improved our knowledge about the pathogenesis of BCC, and several new-generation nonsurgical treatments have been introduced. However, Moh's micrographic surgery remains gold standard for high-risk BCC but is not feasible for all. Choice of treatment for BCC is complex and must take into account tumor type, location, cosmetic outcome, recurrence, comorbidity, patient choice, and feasibility when planning management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Epidemiology
Common Risk Factors
Pathophysiology ...
Diagnosis
Differential Dia...
Histopathology
Imaging
Recurrence and M...
Management
Management of Me...
Follow-up and Pr...
Conclusion
References

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