Hypertrophic and Keloid Scars

Hypertrophic scars (HSs) and keloids are raised, red, and rigid (3 Rs) scars that develop during cutaneous wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing and are characterized by a local abnormal proliferation of fibroblasts with over-production of collagen. Over-expression of growth factors, such as transforming growth factor-beta (TGF-β), and decreased production of molecules that promote matrix breakdown, such as matrix metalloproteinases, appear to be involved in the etiology in both an HS and a keloid. Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics has a strong influence on keloid predisposition, with people of darker skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin complexion having a higher predisposition. Keloids occur mostly on the upper torso, shoulders, head, and neck. Treatment of keloids is often ineffective, but moderate success can be achieved with surgical excision, especially when combined with adjuvant non-surgical management.

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Overview

Definitions

A hypertrophic scar (HS) is a benign exuberant overgrowth of fibro-collagenous tissue. An HS occurs in an area of injury and grows rapidly, but does not go beyond the boundaries of the wound and tends to regress.

Keloids are defined as a benign overgrowth of fibro-collagenous tissue, occurring in an area of dermal injury or chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation (rarely spontaneously). Unlike HSs, keloids continue to enlarge and grow beyond the original boundaries of the injury.

Epidemiology

HSs:

  • 5%–70% of surgical patients: 
    • Up to 90% after deep burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns
    • Higher in people with dark skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • More commonly develop after thermal or traumatic injury involving deep layers of the dermis, or in chronically infected healing wounds

Keloids:

  • Prevalence varies in different racially ethnic groups/ skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin types:
    • Higher predisposition in patients with darker skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin complexion; however, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin melanin content is not the determining factor:
      • White albino prevalence: 0%
      • African albino prevalence: 7.5% 
      • African non-albino prevalence: 8.3%
    • Individuals of Hispanic and African ancestry: 5%–16% 
    • Whites: < 1%
  • Site-specific differences: 
    • Head and neck surgical patients:
      • African Americans: 0.8%
      • Caucasians: 0.1%
    • Women after cesarean section:
      • African Americans: 7.1%
      • Caucasians: 0.5%
  • Familial keloids: 3%–4% of all keloids
  • M:F = 1:1 
  • More common in younger people (20–30-year-olds)

Etiology

  • Multiple genetic factors involved, both in ethnic and familial forms:
    • Multiple, yet-to-be-defined genes appear to be involved in keloid formation.
    • Familial forms have various inheritance patterns, with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables penetrance.
  • Multiple local and individual factors induce hypertrophic scarring and keloid formation: 
    • Local mechanical tension, infection
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension associated with severe keloids

Pathophysiology

Altered wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing causes an imbalance between an increased synthesis of collagen and extracellular matrix (ECM) and decreased degradation of collagen and ECM. 

  • Altered (excessive) ECM synthesis in the 3rd phase of normal wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing (after inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and granulation tissue):
    • Increased fibroblast proliferation and collagen synthesis
  • Over-expression of growth factors:
    • Transforming growth factor-beta (TGF-β)
    • Vascular endothelial growth factor 
    • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue growth factor
  • Decreased production of molecules that promote matrix breakdown (e.g., matrix metalloproteinases):
    • Increased platelet-derived growth factor receptors on fibroblasts
    • Activated insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-like growth factor-1
    • Decreased apoptosis rate of fibroblasts

Pathology

HSs

  • Pathology, gross: elevated scar that stays within the confines of initial injury borders
  • Pathology, microscopic:
    • Thin, well-organized, wavy type III collagen bundles oriented parallel to the epidermis surface 
    • Many myofibroblasts 
    • Abundant acidic mucopolysaccharides

Keloids

  • Pathology, gross: elevated scar that extends beyond the borders of the initial injury, with invasion into the surrounding skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Pathology, microscopic:
    • Disorganized, large, thick, dense (“glassy”) type I and III hypocellular collagen bundles 
    • Few myofibroblasts
    • Poorly vascularized, dilated blood vessels 

Differences

Table: Differences in pathology between HSs and keloids
Category HSs Keloids
Epidemiology

  • Following: 
    • Surgery
    • Deep burn injury
  • Pigmented skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin > lighter skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
  • Following minor injury
  • Acne sites
  • Spontaneous 
Predilection sites

  • Neck
  • Shoulders
  • Anterior chest
  • Knees 
  • Ankles
  • Cheeks
  • Earlobes
  • Shoulders
  • Upper arms
  • Anterior chest
Time course

  • Onset: 4–8 weeks following injury
  • Growth: rapid, up to 6 months 
  • Regression: spontaneous, over a few years
  • Recurrence: low rates
  • Onset: slow, over months or years 
  • Growth: persistence and enlargement over long periods of time
  • Regression: not spontaneous
  • Recurrence: high rates 
Appearance

  • No extension beyond initial wound margins
  • Extend beyond initial wound margins
Histologic characteristics

  • Collagen bundles: thin, well-organized, wavy type III, oriented parallel to the epidermis surface 
  • Many myofibroblasts 
  • Abundant acidic mucopolysaccharides
  • Collagen bundles: disorganized, large, thick, type I and III hypocellular (“glassy”) 
  • Few myofibroblasts
  • Poorly vascularized, dilated blood vessels

Clinical Presentation

Table: Differences in clinical presentation between HSs and keloids
Category HSs Keloids
Description
  • Red
  • Raised
  • Rigid
  • Pruritic
  • Confined to borders of the original injury
  • Red
  • Raised
  • Rigid
  • Pruritic
  • Shiny
  • Smooth
  • Dome shaped
  • Slightly pink or hyperpigmented
  • Extend beyond borders of the initial injury
Predilection sites
  • Neck
  • Shoulders
  • Anterior chest
  • Knees 
  • Ankles
  • Cheeks
  • Earlobes
  • Shoulders
  • Upper arms
  • Anterior chest
Triggers
  • Linear: after trauma or surgery
  • Widespread: after burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns
  • Minor injury
  • Areas of acne or chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • May arise spontaneously 
Growth history
  • Starts growing 4–8 weeks after an injury; then grows rapidly for 6 months
  • Spontaneous regression after a few years
  • Appear slowly over months or years after the inciting stimulus
  • Persist and enlarge over long periods of time
  • No spontaneous regression
Recurrence after excision
  • Low recurrence rate
  • Very high recurrence rate
  • Often with larger keloids

Diagnosis and Management

Diagnosis

  • Clinical diagnosis, based on:
    • History
    • Scar shape and size
    • Growth pattern
  • If uncertain, a skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin biopsy is performed to exclude other serious conditions.

Management

  • Treatment of HSs has better success:
    • Intralesional corticosteroids (or tapes and plasters for smaller scars)
    • Surgical resection, with or without skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin grafting or application of fibrin glue scaffold containing autologous fibroblasts and keratinocytes
  • Treatment of keloids is non-standardized and often ineffective, but moderate success can be achieved by using 1 or more therapies, including:
    • Corticosteroid injections (or tapes, plasters for small keloids)
    • Silicone gel sheeting
    • Pressure therapy
    • Radiation
    • Cryotherapy
    • Laser therapy
    • Intralesional fluorouracil
    • Immunomodulators (e.g., topical imiquimod)
    • Excision to debulk the scar (possible skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin grafting if the area is well vascularized): Adjuvant therapy is necessary or the keloid will recur, often growing to a larger size.

Prevention

For persons with a history of hypertrophic or keloid scarring: 

  • Avoid unnecessary trauma, including minor cosmetic procedures (e.g., ear piercing, removal of benign skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions). 
  • Acne or any skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin infections: 
    • Treat early.
    • Avoid chronicity.
  • Acne keloidalis nuchae: 
    • Avoid closely fitting caps or coverings.
    • No short haircuts or close shaves
    • Practice good topical hygiene with antimicrobial (chlorhexidine or benzoyl peroxide–based) cleansers/shampoos.
  • After necessary surgery: 
    • Keep the wound moist and covered.
    • Avoid stretching tension on the wound.
    • Avoid sun exposure to decrease hyperpigmentation.

Differential Diagnosis

  • Nodular scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma (NS): rare variant of scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma usually involving the chest, back, neck, and proximal portion of extremities, and is characterized by multiple firm, non-tender nodules or plaques with a histologic appearance similar to a keloidal scar. Nodular scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma usually occurs with systemic sclerosis Systemic sclerosis Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma and with typical laboratory findings of antinuclear antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins in a homogenous pattern (titer 1:320) and positive anti-Scl70.
  • Dermatofibrosarcoma protuberans (DFSP): rare cutaneous sarcoma that presents as a slowly growing plaque or nodule. Histology shows uniform spindle cells in long fascicles arranged in parallel to the epidermis, often showing a storiform pattern. Immunohistochemistry (CD34+) and molecular studies (t(17;22)) can support the diagnosis.
  • Giant cell fibroblastoma (GCF): rare, subcutaneous low-grade sarcoma of childhood, considered to be a juvenile form of DFSP, with spindle-shaped fibroblasts and multinucleated sarcomatous cells.
  • Lobomycosis: chronic tropical fungal infection of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and subcutaneous tissue, seen in Latin America. Presents as keloid-like nodules or plaques on exposed skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin. Diagnosis is easily made by biopsy.

References

  1. Inflammation and Repair. (2020). In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). Robbins & Cotran Pathologic Basis of Disease. (10 ed., p. 110). Elsevier, Inc.
  2. Aaron, D.M. (2020). Keloids—Dermatologic disorders. MSD Manual Professional Edition. https://www.msdmanuals.com/professional/dermatologic-disorders/benign-skin-tumors,-growths,-and-vascular-lesions/keloids
  3. Limandjaja, G. C., Niessen, F. B., Scheper, R. J., & Gibbs, S. (2020). The keloid disorder: Heterogeneity, histopathology, mechanisms and models. Frontiers in Cell and Developmental Biology, 8. https://doi.org/10.3389/fcell.2020.00360
  4. Marneros. A.G., Norris, J.E.C., Olsen, B.R., & Reichenberger, E. (2001). Clinical Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics of Familial Keloids. Arch Dermatol. 137(11), 1429–1434. Elsevier, Inc.
  5. Gauglitz, G. G., Korting, H. C., Pavicic, T., Ruzicka, T., & Jeschke, M. G. (2011). Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Molecular medicine (Cambridge, Mass.), 17(1-2), 113–125. https://doi.org/10.2119/molmed.2009.00153
  6. Morihara, K., Takai, S., Takenaka, H., et al. (2006). Cutaneous tissue angiotensin- converting enzyme may participate in pathologic scar formation in human skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin. J Am Acad Dermatol. 54(2), 251–257.
  7. Ogawa, R., Arima, J., Ono, S., & Hyakusoku, H. (2013). CASE REPORT Total Management of a Severe Case of Systemic Keloids Associated With High Blood Pressure ( Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension): Clinical Symptoms of Keloids May Be Aggravated by Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension. Eplasty, 13, e25.
  8. Betarbet, U., & Blalock, T. W. (2020). Keloids: A Review of Etiology, Prevention, and Treatment. The Journal of Clinical and Aesthetic Dermatology, 13(2), 33–43.

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