Hypertrophic and Keloid Scars

Hypertrophic scars (HSs) and keloids are raised, red, and rigid (3 Rs) scars that develop during cutaneous 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 has a strong influence on keloid predisposition, with people of darker 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 (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
    • Higher in people with dark 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 types:
    • Higher predisposition in patients with darker skin complexion; however, 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 penetrance.
  • Multiple local and individual factors induce hypertrophic scarring and keloid formation: 
    • Local mechanical tension, infection
    • Hypertension associated with severe keloids

Pathophysiology

Altered 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 (after 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 growth factor
  • Decreased production of molecules that promote matrix breakdown (e.g., matrix metalloproteinases):
    • Increased platelet-derived growth factor receptors on fibroblasts
    • Activated 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
  • 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 HSsKeloids
Epidemiology

  • Following: 
    • Surgery
    • Deep burn injury
  • Pigmented skin > lighter 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 HSsKeloids
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
  • Minor injury
  • Areas of acne or chronic 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 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 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 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 lesions). 
  • Acne or any 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 (NS): rare variant of 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 usually occurs with systemic sclerosis and with typical laboratory findings of antinuclear antibodies 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 and subcutaneous tissue, seen in Latin America. Presents as keloid-like nodules or plaques on exposed 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 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. 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): Clinical Symptoms of Keloids May Be Aggravated by 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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