Basal cell carcinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maneesha Nandimandalam, M.B.B.S.[2]

Overview

Basal cell carcinoma is one of the most common skin cancers. It is commonly known as rodent ulcer due to its distinct morphology characterized by pearly pink nodules with telangiectasias, rolled borders, and central crusting with or without an ulcerating lesion. The majority common cause for the development of the basal cell carcinoma involves radiation exposure and mutations that involve many genes including sonic hedgehog gene, PTCH1 gene, and other gain-of-function mutations which further depend on the subtypes such as nodular, superficial, Infundibulocystic, fibroepithelial, morpheaform, infiltrative, micronodular, and basosquamous basal cell carcinomas.

Pathophysiology

Pathogenesis

The exact pathogenesis of basal cell carcinoma is not completely understood

Genetics

The development of basal cell carcinoma is the result of multiple genetic mutations such as sonic hedgehog pathway mutations, and PTCH1 gene mutations

• A number of aberrations involving the sonic hedgehog signaling pathway(SHH) are noted.
• This pathway is vital for the regulation of cell growth, and differentiation and loss of inhibition of this pathway is associated with development of basal cell cancer.
• The majority of mutations in sporadic basal cell carcinoma and basal cell nevus syndrome(BCNS) patients occur in PTCH1 gene, a protein that inhibits smoothened gene (SMO).
• The second most common mutation in sporadic basal cell carcinoma and basal cell nevus syndrome(BCNS) patients are gain-of-function mutations of the smoothened gene (SMO).
• Loss of PTCH1 results in the failure of Smoothened inhibition, subsequently leading to increases in GLI1 levels, changes in transcription, and subsequent tumorigenesis.
• Gain-of-function smoothened(SMO) mutations also leads to increased GLI1 levels and tumorigenesis

Loss of PTCH1

Gain of function SMO

Lack of SMO inhibition

Activation of SMO-GLI signaling

↑GLI1 levels

Changes in transcription

Tumorigenesis

Sonic hedgehog signaling pathway. SHH ligand binds to and inhibits the PTCH transmembrane protein. The inhibition of PTCH relieves suppression of / (Smoothened), which then activates the GLI transcription factors. The GLI proteins translocate from the cytoplasm to the nucleus, where they drive gene transcription. (Courtesy of Alexander G. Marzuka, MD),https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445438/

Other Genetic Changes:

• Point mutations in the TP53 gene, the tumor supressor gene are the second most common genetic alteration noticed in BCCs
• Some mutations in the CDKN2A locus and in ras gene family (H-ras, K-ras, and N-ras) are also identified in a smaller proportion of sporadic BCCs

Enviromental Exposure

• Basal cell carcinomas develop in the basal cell layer of the skin.
• Cumulative DNA damage caused by chronic sunlight exposure results in DNA mutations that predispose to the development of basal cell carcinoma.
• While DNA repair eliminates most UV-induced damage, not all cross-links are excised, which eventually results in mutations.
• Apart from the mutagenesis, sunlight depresses the local immune system, possibly decreasing immune surveillance for new tumor cells.

Gross and microscopic pathology

• On gross and microscopic histopathological analysis the characteristic findings of basal cell carcinoma are described as below:
• Basal cell carcinoma pathological features mainly depend upon the subtype. The following table summarizes them:

Subtypes of BCC	Gross features		Microscopic features
	Findings	Images	Findings	Images
Nodular	Shiny, pearly papule or nodule with a smooth surface Rolled borders and telangiectasias Mostly seen on the head and neck	M. Sand, D. Sand, C. Thrandorf, V. Paech, P. Altmeyer, F. G. Bechara [CC BY 2.0 (https://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons	Discrete nests of malignant basaloid cells in the dermis Peripheral palisading Mucoid stroma containing plump spindle cells	No machine-readable author provided. KGH assumed (based on copyright claims). [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons,https://upload.wikimedia.org/wikipedia/commons/b/b6/Basal_cell_carcinoma_histopathology_%283%29.jpg
Superficial	Well-circumscribed Erythematous thin plaque or patch with scale Central clearing and thin rolled borders Most common on the trunk	Kelly Nelson (Photographer) [Public domain], via Wikimedia Commons,https://upload.wikimedia.org/wikipedia/commons/3/32/Basal_cell_carcinoma%2C_superficial.jpg	Multiple lobular foci of basaloid palisading keratinocyte tumors These are usually attached superficially to the epidermis with a myxoid stroma and band-like lichenoid infiltrate	machine-readable author provided. KGH assumed (based on copyright claims). [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons
Infundibulocystic	Well-circumscribed pearly papule Most common on the head and neck region		Well-circumscribed Anastomosing strands of basaloid cells and scattered infundibulum-like cystic structures
Fibroepithelial	Skin-colored/erythematous Sessile plaque/pedunculated papulonodule They have a predilection for trunk region		Multiple collections of delicate strands of epidermal basaloid keratinocytes These are usually arranged in a reticular pattern within a spindle cell stroma
Morpheaform	Infiltrated plaque with poorly defined borders and shiny surface Most common on head and neck region	Dermatology Centre, Salford Royal Hospital, NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK.	Thin cords of basaloid cells surrounded by a sclerotic collagenous stroma Absent peripheral palisading and stromal cleft formation Positive staining of tumor stroma with smooth muscle alpha-actin	Department of Pathology, Columbia University Medical Center, New York, USA
Infiltrative	Poorly defined Indurated, flat or depressed plaque with white, yellow, or pale pink color They may have overlying crusts, erosions, ulcerations, or papules	Kelly Nelson (Photographer) [Public domain], via Wikimedia Commons,https://upload.wikimedia.org/wikipedia/commons/9/9b/Basal_cell_carcinoma_%281%29.jpg,	Thin cords with angulated ends of few basaloid keratinocytes Usually embedded in a classic mucinous/myxoid stroma
Micronodular	Erythematous macule or thin papule/plaque		Multiple small aggregates of basaloid cells within the dermis, with subtle peripheral palisading and retraction artifact
Basosquamous	Majority found on the head and neck		Well-defined nodular or superficial BCC component overlying an invasive front showing basal cell carcinoma and squamous cell carcinoma histologic feature

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