Background

Keloids, or so-called "proud flesh" are a variant of hypertrophic scars, representing one spectrum of the healing process. We are all familiar with the appearance of these unsightly scars. They usually develop over areas of the back, deltoid and presternal areas, and ear lobes. Risk factors associated with keloid formation include black race, increased skin tension in a wound, younger patients <30 yrs, and any predisposition to hypertrophic scars.

Histologically, keloids represent one spectrum of hypertrophic scars and have characteristic thickened eosinophilic collagen bundles arranged in haphazardly intersecting fasicles. These fibroblasts synthesize normal amounts of collagen but there are increased numbers. In addition, the normal degradation process of this collagen is diminished by proteoglycan and protease inhibitors. Keloids can be excised but may result in regrowth of a larger lesion unless a concurrent treatment is enacted such as steroid injection or laser treatment. The decision to treat a keloid is a personal one and must be made with the treating physician.

OUTLINE

Epidemiology
Pathogenesis
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Scar, Hypertrophic scar, Proud Flesh
INCIDENCE/PREVALENCE	Common
EPIDEMIOLOGIC ASSOCIATIONS
Clinical Genetics of Familial Keloids Alexander G. Marneros; James E. C. Norris, MD; Bjorn R. Olsen, MD, PhD; Ernst Reichenberger, PhD	Arch Dermatol. 2001;137:1429-1434 Abstract quote Background Keloids are proliferative fibrous growths that result from an excessive tissue response to skin trauma. Most keloids occur sporadically, but some cases are familial. However, the genetics of keloid formation have only rarely been documented, and the mode of inheritance is not known. Objective To elucidate the clinical genetic characteristics of keloid wound-healing disorder. Observations We studied the clinical and genetic characteristics of 14 pedigrees with familial keloids. The ethnicity of these families is mostly African American (n = 10), but also white (n = 1), Japanese (n = 2), and African Caribbean (n = 1). The pedigrees account for 341 family members, of whom 96 displayed keloids. Of the affected family members, 36 are male and 60 are female. The age of onset varies from early childhood to late adulthood. There is variable expression of keloids within the same families: some affected members have only minor earlobe keloids, whereas others have very severe keloids affecting large areas of the body. In the described pedigrees, 7 individuals are obligate unaffected carriers, revealing nonpenetrance in about 6.8% of keloid gene carriers. Syndromes associated with keloids, namely Rubinstein-Taybi and Goeminne syndrome, were not found in these families. Additionally, linkage to the gene loci of these syndromes and X-chromosomal linkage were excluded. Conclusions The pattern of inheritance observed in these families is consistent with an autosomal dominant mode with incomplete clinical penetrance and variable expression. This is the most comprehensive collection of keloid families described to date, and it allows for the first time the elucidation of the clinical genetic characteristics of the familial form of this wound-healing disorder.

PATHOGENESIS	CHARACTERIZATION
GLI-1
Are keloids really “gli-loids”?: High-level expression of gli-1 oncogene in keloids Amy Kim, MD Josh DiCarlo, MD Cynthia Cohen, MD, etal Atlanta, Georgia, and London, England	J Am Acad Dermatol 2001;45:707-11. Abstract quote Background: Keloids are a common lesion arising from sites of previous trauma and are a considerable source of morbidity because of continued growth of lesions, pruritus, and physical appearance. They consist of mesenchymal cells embedded in a stroma of disordered collagen matrix. Clinically, keloids are distinguished from scars in that keloids demonstrate continued growth over the borders of the original injury. Keloids appear with increased frequency in patients of African and Asian descent. Currently, no entirely satisfactory method of treatment exists for these lesions. Recently, a patient who was enrolled in a clinical trial of topical tacrolimus for atopic dermatitis applied this drug to a keloid and noted clearing. Objective: Based on this clinical observation and the observation that rapamycin, a chemically similar compound to tacrolimus, is known to inhibit signaling from the gli-1 oncogene, we examined keloids and scars for expression of Gli-1 protein. Methods: Skin sections from keloids and scars were examined by immunohistochemical staining for gli-1. To further confirm the presence of gli-1 expression in keloids, reverse transcriptase-polymerase chain reaction was carried out. Results: Expression of gli-1 was strongly elevated in keloids compared with scars. Conclusion: These results provide a rationale for the treatment of keloids with topical rapamycin analogs, including tacrolimus. Clinical trials of topical tacrolimus are warranted.
KERATINOCYTES
Keratinocytes promote proliferation and inhibit apoptosis of the underlying fibroblasts: an important role in the pathogenesis of keloid. Funayama E, Chodon T, Oyama A, Sugihara T. Department of Plastic and Reconstructive Surgery, Hokkaido University School of Medicine, Sapporo, Japan.	J Invest Dermatol. 2003 Dec;121(6):1326-31. Abstract quote   Interactions between epidermal keratinocytes and dermal fibroblasts play an important role in regulating tissue homeostasis and repair. Nevertheless, little is known about the role of keratinocytes in the pathogenesis of keloid. In this study, we investigated the influence of normal skin- and keloid-derived keratinocytes on normal skin- and keloid-derived fibroblasts utilizing a serum-free indirect coculture system. The keloid-derived fibroblasts showed a greater proliferation and minimal apoptosis when cocultured with normal skin- or keloid-derived keratinocytes, and the results were most significant in the latter. This difference was not observed when the fibroblasts were treated with conditioned medium obtained from normal skin- and keloid-derived keratinocytes. Nevertheless, conditioned medium-treated groups showed more proliferation and less apoptosis compared to the nonconditioned medium-treated control groups. We also analyzed the profile of factors involved in cell growth and apoptosis in fibroblasts cocultured with keratinocytes. Extracellular signal-regulated kinase and c-Jun N-terminal kinase phosphorylations and expression of Bcl-2 and transforming growth factor-beta1 were all significantly upregulated in the fibroblasts cocultured with keloid-derived keratinocytes. Together, these results strongly suggest that the overlying keratinocytes of the keloid lesion play an important role in keloidogenesis by promoting more proliferation and less apoptosis in the underlying fibroblasts through paracrine and double paracrine effects.
MATRIX METALLOPROTEINASE-9
Release and activation of matrix metalloproteinase-9 during in vitro mechanical compression in hypertrophic scars. Reno F, Grazianetti P, Stella M, Magliacani G, Pezzuto C, Cannas M. Human Anatomy Laboratory, Medical Sciences Department, University of Eastern Piedmont "A. Avogadro," Via Solaroli 17, 28100 Novara, Italy.	Arch Dermatol 2002 Apr;138(4):475-8 Abstract quote OBJECTIVE: To investigate induction of matrix metalloproteinases (MMPs) during mechanical compression of hypertrophic scars. Mechanical pressure blocks hypertrophy inducted on extracellular matrix in scars by a mechanism that involves MMP-2 (gelatinase A) and MMP-9 (gelatinase B). DESIGN: We assayed conditioned media obtained from normotrophic and hypertrophic scars during 24 hours of in vitro mechanical compression using gelatin zymography. SETTING: Scars from various areas of the bodies of hospitalized patients. PATIENTS: We obtained 3 normotrophic and 7 hypertrophic biopsy specimens from 10 patients (5 men and 5 women). INTERVENTION: In vitro compression at a pressure of 35 mm Hg/cm(2) for 24 hours. MAIN OUTCOME MEASURES: Vitality of scars was analyzed by means of lactic dehydrogenase test; medium samples were collected for zymographic analysis of MMP activity. RESULTS: We found MMP-2 in basal (uncompressed) samples from normotrophic and hypertrophic scars. Mechanical compression induced MMP-9 release and activation (range, 86.7%-78.7%) in hypertrophic scars after 4 hours. CONCLUSION: Production, release, and activation of MMP-9 in hypertrophic scars could be an effector mechanism responsible for hypertrophy regression induced by mechanical compression.
Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds. Mirastschijski U, Impola U, Jahkola T, Karlsmark T, AGren MS, Saarialho-Kere U. Department of Surgery, Malmo University Hospital, University of Lund, Malmo, Sweden.	Hum Pathol 2002 Mar;33(3):355-64 Abstract quote It has been hypothesized that excessive activity of matrix metalloproteinases (MMPs), in particular the gelatinases MMP-9 and MMP-2, contributes to poor healing of chronic skin ulcers. We compared MMP-9 and MMP-2 in wound margin biopsies of standardized acute partial-thickness wounds in healthy volunteers (n = 6) and in venous leg ulcer patients (n = 12) with those of chronic wounds of different etiologies (n = 34) by a combination of specific analyses of activity and protein localization. We also studied MMP-14 by immunohistochemistry and in situ hybridization in parallel. Neither MMP-9 (P =.814) nor MMP-2 (P =.742) endogenous activities differed significantly between acute and chronic wound tissues. Acute wound healing was characterized by induction of MMP-9 in the advancing epithelium. In chronic wounds, prominent MMP-9 immunostaining was seen in neutrophils and macrophages in the ulcer bed, but virtually no MMP-9 was detected in wound edge keratinocytes. MMP-2 was increased and activated with acute wound age. MMP-2 was found abundantly in dermal fibroblasts and endothelial cells beneath, but not in new epithelium of acute and chronic wounds. MMP-14 mRNA or protein was detected solely in the stroma of both acute and chronic wounds. In conclusion, the overall activity of gelatinases MMP-9 and MMP-2 was not increased in chronic wounds compared to normally healing wound tissues. Chronic nonhealing wounds may not be caused by excessive gelatinase activity, but are distinguished from healing wounds by an unfavorable distribution and persistance of MMP-9.
UROKINASE-TYPE PLASMINOGEN ACTIVATOR
Expression of urokinase-type plasminogen activator and its receptor in keloids. Leake D, Doerr TD, Scott G. Division of Otolaryngology-Head and Neck Surgery, University of Rochester School of Medicine and Dentistry, 601 Elmwood Drive, Rochester, NY 14642, USA.	Arch Otolaryngol Head Neck Surg. 2003 Dec;129(12):1334-8. Abstract quote   BACKGROUND: The urokinase-mediated plasminogen activation (uPA) system plays a central role in a number of cellular processes including tissue remodeling, cell migration, and angiogenesis. Elevated uPA activity has also been seen with tumor invasion and metastasis in a variety of malignancies. Keloids represent an aberrant form of wound healing characterized by uncontrolled growth with invasion beyond the margins of the original wound. The regulation of this cellular process remains poorly understood. We hypothesize that keloids will have increased staining percentage for uPA and its receptor (uPAR) compared with normal scars. To our knowledge, no previous studies have examined the relationship of uPAR in keloid formation. DESIGN: Analysis of uPAR expression by immunohistochemistry in paraffin sections from 20 keloids and 18 normal scars. Expression was graded by a dermatopathologist according to percentage of cells staining for uPAR. SETTING: University Medical Center (Division of Otolaryngology-Head and Neck Surgery) and the Department of Dermatology at the University of Rochester Medical and Dental School, Rochester, NY. RESULTS: Of the 20 keloids, 8 (40%) strongly expressed uPAR (>50% of cells), while only 4 (22%) of 18 normal scars had similar staining. More than half of the normal scars stained minimally for uPAR (<5% staining). There was a strong expression of uPAR in the extracellular matrix in 14 (70%) of the 20 keloids, while no scar showed uPAR in the extracellular matrix. CONCLUSION: Our observation suggests that the uPA system is involved in the expansion of keloids beyond the wound margins in part through the degradation of the extracellular matrix, a finding that is supported by the strong expression of uPAR in the extracellular matrix and collagenous cords in most keloids studied.

HISTOPATHOLOGICAL VARIANTS	CHARACTERIZATION
GENERAL
Histopathological Differential Diagnosis of Keloid and Hypertrophic Scar. Lee JY, Yang CC, Chao SC, Wong TW. Department of Dermatology, National Cheng Kung University Hospital, Tainan, Taiwan.	Am J Dermatopathol. 2004 Oct;26(5):379-384. Abstract quote   Distinguishing hypertrophic scar (HS) from keloid histopathologically is sometimes difficult because thickened hyalinized collagen (keloidal collagen), the hallmark of keloid, is not always detectable and α-smooth muscle actin (α-SMA), a differentiating marker of HS, is variably expressed in both forms of scar. The aim of this study was to investigate additional distinguishing features to facilitate differentiation between keloid and HS. We compared various histologic features and the expression of α-SMA in 40 specimens of keloid and 10 specimens of HS. The features more commonly seen in keloids were: (a) no flattening of the overlying epidermis, (b) no scarring of the papillary dermis, (c) presence of keloidal collagen, (d) absence of prominent vertically oriented blood vessels, (e) presence of prominent disarray of fibrous fascicles/nodules, (f) presence of a tongue-like advancing edge underneath normal-appearing epidermis and papillary dermis, (g) horizontal cellular fibrous band in the upper reticular dermis, and (h) prominent fascia-like fibrous band. The last three features were found in keloid specimens only, including the ones lacking detectable keloidal collagen. Our study confirmed the diagnostic value of keloidal collagen, but it was only found in 55% of keloid specimens. α-SMA expression was found in both HS (70%) and keloid (45%), thus it would not be a differentiating marker. In scars with no detectable keloidal collagen, the presence of the following feature(s) favors the diagnosis of keloid: non-flattened epidermis, non-fibrotic papillary dermis, a tongue-like advancing edge, horizontal cellular fibrous band in the upper reticular dermis, and prominent fascia-like band.
ATYPICAL MELANOCYTIC HYPERPLASIA
Melanocytic hyperplasia in scars. A histopathological investigation of 722 cases. Duve S, Schmoeckel C, Burgdorf WH. Dermatopathology Laboratory, Technical University of Munich, Germany.	Am J Dermatopathol 1996 Jun;18(3):236-40 Abstract quote We studied 722 reexcision scars of benign and malignant lesions (except melanocytic lesions) excised over a 24-month period. The formalin-fixed, paraffin-embedded tissue sections were examined histologically and immunohistochemically. The histological features of melanocytic hyperplasia were present in 59 cases (8%), 56 from the sun-exposed skin of the face and neck and three from the trunk [p < 0.00001]. The most common sites were the nose and lower eyelids, but the forehead was also frequently involved. Of the 59 patients, 41 were women (p < 0.0001). Basal cell carcinoma was the most frequent original lesion in both sexes (80%). No melanocytic hyperplasia was found in 663 cases (298 on the trunk and extremities and 365 on the head and neck). We have seen this reaction pattern following reexcision of melanocytic lesions as well. Thus, interpreting reexcision margins when lentigo maligna or similar lesions are reexcised may be fraught with difficulty. It is important for pathologists and dermatopathologists to recognize this phenomenon because histologically the presence of increased numbers of large melanocytes could be misinterpreted as melanoma in situ.

SPECIAL STAINS/ IMMUNO-HISTOCHEMISTRY	CHARACTERIZATION
GENERAL
A light microscopic and immunohistochemical evaluation of scars Nandan V. Kamath Adrian Ormsby Wilma F. Bergfeld Nancy S. House	J Cutan Pathol 2002;29:27 Abstract quote Background: Scars are commonly encountered by dermatopathologists and usually do not present a diagnostic challenge. However, in some cases, the pathologist may need to consider a broad differential diagnosis including fibrohistiocytic tumors, smooth muscle tumors, myofibroblastic proliferations and desmoplastic malignant melanoma. Although specific histologic aspects of scars have been well studied, a complete histochemical profile of scars, especially at various stages of evolution, has not been described. Methods: Twenty-five cases of scars including 8 normal scars, 5 hypertrophic scars and 12 keloids were studied. Sections were examined with Verhoeff van Giesson, colloidal iron, Giemsa, smooth muscle actin (SMA), CD34, Factor XIIIa and S-100. Results: All scars were negative for CD34 expression. Factor XIIIa immunostaining identified only rare dermal dendrocytes. S-100 was absent in 23 of 25 cases and stained scattered cells (less than 10%) in the other 2 cases. SMA was positive in 14 of 25 cases with 6 of these showing staining of up to 50% of spindled cells. Elastic fibers were markedly reduced or absent in all cases, mucin showed moderate or marked staining in three-fourths of the cases and dermal mast cells showed a moderate increase in 5 cases. Conclusions: These findings confirm prior reports that negative staining with CD34, Factor XIIIa and S-100 can help differentiate scars from dermatofibrosarcoma protuberans, dermatofibroma and desmoplastic malignant melanoma, respectively. SMA staining is much more variable and requires careful interpretation.
S100 POSITIVE CELLS
S100-positive spindle cells in scars: a diagnostic pitfall in the re-excision of desmoplastic melanoma. Chorny JA, Barr RJ. Dermatopathology Laboratory, University of California Irvine Medical Center, Orange, California 92868, U.S.A.	Am J Dermatopathol. 2002 Aug;24(4):309-12. Abstract quote   Distinguishing desmoplastic melanoma (DM) from scar tissue on routine microscopy can be difficult, especially in re-excision specimens, and S100 immunohistochemistry has been recommended as a useful adjunct. The purpose of this study is to evaluate the extent and nature of S100 positivity in scars. In this study, formalin-fixed paraffin archival tissues were evaluated with immunohistochemistry. Ten re-excision specimens of previously biopsied nonnevomelanocytic lesions were immunostained with the S100 and CD57 (Leu 7) antibodies. In 9 of the 10 cases, the scars contained S100-positive spindle cells, but there were no cases with CD57+ cells. Ten re-excised atypical nevi and 10 re-excised melanomas were also immunostained for the S100 protein, and all 20 cases contained S100-positive spindle cells within the scars. There was a trend toward quantitatively more S100-positive spindle cells in these nevomelanocytic re-excisions. To evaluate the nature of the spindle cells, scars from two of the nonnevomelanocytic re-excisions were further analyzed utilizing immunostains for glial fibrillary acidic protein, HMB-45, Melan-A, CD1a, factor XIIIa, and neuron specific enolase. In both scars, neuron specific enolase diffusely stained the fibroblast population, but the remaining immunostains were negative in the scar. The presence of S100-positive spindle cells in scars represents a potential diagnostic pitfall, particularly in the evaluation of re-excision specimens of DM.
S100 expression in cutaneous scars: a potential diagnostic pitfall in the diagnosis of desmoplastic melanoma. Robson A, Allen P, Hollowood K. Department of Cellular Pathology, Level 1, John Radcliffe Hospital, Headley Way, Oxford, UK.	Histopathology. 2001 Feb;38(2):135-40. Abstract quote   AIMS: The histological distinction of desmoplastic melanoma from cutaneous scar tissue, particularly in the context of re-excision specimens or possible recurrence, may be very difficult. Immunostaining for S100 protein is often used to discriminate although there are little data on S100 expression in scar tissue. The aim of this study was to assess whether S100-positive cells are present in dermal scars and, if so, their extent, distribution and nature. METHODS AND RESULTS: Twenty-two re-excision specimens of previously biopsied nonmelanocytic skin lesions were reviewed. Formalin-fixed paraffin-embedded sections containing dermal scars were stained by a standard ABC immunoperoxidase technique for S100 protein, CD1a and neurofilaments. The distribution and morphology of positive cells within the dermal scar tissue were documented. Cells expressing S100 protein were identified within the scars of 21 of the 22 cases. The number of S100-positive cells varied between cases but in four specimens was substantial. They displayed a variety of morphological appearances but the majority were spindle-shaped. A few showed mild cytological atypia. It is suggested that the majority represent Schwann cells with a minority of Langerhans cells and cells of uncertain lineage. CONCLUSION: S100-positive cells, including spindle cells showing mild atypia, are found in cutaneous scars. S100 staining of re-excision specimens or putative recurrences of desmoplastic melanoma should be interpreted with caution.
Atypical cells in human cutaneous re-excision scars for melanoma express p75NGFR, C56/N-CAM and GAP-43: evidence of early Schwann cell differentiation. Trejo O, Reed JA, Prieto VG. Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.	J Cutan Pathol. 2002 Aug;29(7):397-406. Abstract quote   BACKGROUND: A common problem in the routine examination of melanoma re-excision scars occurs when a few or rare mildly atypical cells are present within the scar, raising the question of residual disease. Little is known about the derivation of these cells. Because the normal cutaneous wound-healing process is reparative, we hypothesized that these atypical cells may be reactive proliferating Schwann cell precursors. METHODS: The expression of the Schwann cell differentiation markers p75NGFR, CD56/N-CAM and GAP-43 was examined by immunohistochemistry in scars of wide local re-excisions for melanoma and non-melanoma tumors. Expression of S100, gp100 (with HMB45) and MART1 was also analyzed by immunohistochemistry. RESULTS: All melanoma and non-melanoma re-excision specimens contained mildly atypical, spindled or epithelioid cells within the scar. They varied in number from case to case and expressed S100, p75NGFR, CD56/N-CAM or GAP-43 but not gp100 (with HMB45) or MART1. Rare epithelioid non-melanoma cells within the superficial dermis expressed MART-1. CONCLUSIONS: Atypical cells are present in re-excision scars from melanoma and non-melanoma cases. They demonstrate early Schwann cell differentiation and appear to proliferate during the scarring process. The use of anti-MART-1 alone in the examination of melanoma re-excisions specimens may be inadequate as it may label rare, superficially located, non-melanoma cells within the scar.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
DESMOPLASTIC MELANOMA
Histologic differentiation of desmoplastic melanoma from cicatrices. Kaneishi NK, Cockerell CJ. Division of Dermatopathology, University of Texas Southwestern Medical Center, Dallas, USA.	Am J Dermatopathol. 1998 Apr;20(2):128-34. Abstract quote   Desmoplastic malignant melanoma (DMM) is a rare variant of melanoma that can be very difficult to diagnose correctly both clinically and histologically. The problem is compounded by the fact that many lesions persist at previous biopsy or excision sites so that scar tissue is often present admixed with or adjacent to the spindle cell neoplasm which may exhibit fibroblastic differentiation itself. In order to assess this problem, we compared and contrasted the histologic features of six DMM with 15 examples of cicatrices from various sources. Mature scars were readily differentiated from DMM by light microscopy. In contrast, immature scar and DMM had many features in common including hypercellularity, nodular lymphoid infiltrates, myxoid stroma, and atypical nuclei. The presence of a melanocytic proliferation within the epidermis above the dermal component, neurotropism, and S-100 and/or HMB-45 positivity of neoplastic cells were the only features that permitted reliable differentiation between the two. Clinical correlation and review of previous biopsy specimens are crucial in preventing a delayed diagnosis of DMM. Re-excision is advised in all questionable cases.
NODULAR SCLERODERMA
Nodular scleroderma: case report and literature review. Cannick L 3rd, Douglas G, Crater S, Silver R. Department of Internal Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA.	J Rheumatol. 2003 Nov;30(11):2500-2 Abstract quote.   OBJECTIVE: To describe a unique case of scleroderma (SSc) presenting as multiple keloidal nodules and early-onset osteoarthritis (OA), and to summarize the clinical and serological data for 13 similar patients reported in the English literature since 1966. METHODS: MEDLINE review of the literature over a 35-year period (1966-2002) revealed 13 cases of nodular SSc. We describe a case of nodular SSc in a 40-year-old African-American male with localized SSc who developed progressive skin thickening and keloidal nodules on the arms, hands, chest, abdomen, and thighs with advanced osteoarthritis of the hips. RESULTS: In all 14 cases, diagnosis was made based on skin biopsy and evidence of keloid (nodule) formation. Ten cases occurred in women and 4 in men, with ages ranging from 9 to 66 years and a mean age of 38.9 years. The ethnicity of the patients was given in only 5 of the 13 previously reported cases. Including our patient, 4 were of African descent, and 2 were Caucasian. Most patients had symptoms of SSc consisting of arthralgias (n = 10), sclerodactyly (n = 9), Raynaud's phenomenon (n = 8), digital pitting and/or calcinosis (n = 5), shortness of breath with pulmonary fibrosis (n = 5) or pulmonary hypertension (n = 1), dysphagia or reflux (n = 3), renal disease (n =3), and elevated erythrocyte sedimentation rate (n = 3). CONCLUSION: Nodular SSc is a rare variant that presents with lesions that clinically resemble keloids. OA, as documented in the present case, does not appear to be a typical feature of nodular SSc.

 

TREATMENT	CHARACTERIZATION
GENERAL
Topical treatments for hypertrophic scars. Zurada JM, Kriegel D, Davis IC. Columbia University College of Physicians and Surgeons, New York, New York, USA.	J Am Acad Dermatol. 2006 Dec;55(6):1024-31. Epub 2006 Sep 18. Abstract quote Hypertrophic scars represent an abnormal, exaggerated healing response after skin injury. In addition to cosmetic concern, scars may cause pain, pruritus, contractures, and other functional impairments. Therapeutic modalities include topical medications, intralesional corticosteroids, laser therapy, and cryosurgery. Topical therapies, in particular, have become increasingly popular because of their ease of use, comfort, noninvasiveness, and relatively low cost. This review will discuss the properties and effectiveness of these agents, including pressure therapy, silicone gel sheeting and ointment, polyurethane dressing, onion extract, imiquimod 5% cream, and vitamins A and E in the prevention and treatment of hypertrophic scars.
CRYOTHERAPY
Intralesional cryotherapy for enhancing the involution of hypertrophic scars and keloids. Har-Shai Y, Amar M, Sabo E. Unit of Plastic Surgery and Department of Pathology, Carmel Medical Center, Haifa, Israel.	Plast Reconstr Surg. 2003 May;111(6):1841-52. Abstract quote   Although therapeutic management of hypertrophic scars and keloids using contact or spray cryosurgery has yielded significant improvement or complete regression of hypertrophic scars and keloids, it requires one to 20 treatment sessions. This study was designed to assess the clinical safety and efficacy of an intralesional needle cryoprobe method in the treatment of hypertrophic scars and keloids.Ten patients, ranging in age from 3 to 54 years, with a total of 12 hypertrophic scars and keloids of more than 6 months duration and of diverse causes, were included in this study. The 18-month trial evaluated volume reduction of the hypertrophic scars and keloids after a single session of intralesional cryotherapy. Objective (hardness and color) and subjective (pain/tenderness and itchiness/discomfort) parameters were examined on a scale of 0 to 3 (low score was better). Pretreatment and posttreatment histomorphometric studies of the collagen fibers included spectral picrosirius red polarization and fast Fourier transformation orientation index. A specially designed cryo-needle was inserted into the long axis of the hypertrophic scars and keloids so as to maximize the volume of the hypertrophic scars and keloids to be frozen. The cryo-needle was connected by an adaptor to a cryogun filled with liquid nitrogen, which was introduced into the cryoprobe, thereby freezing the hypertrophic scars and keloids. After the hypertrophic scars and keloids were completely frozen, the cryoprobe defrosted and was withdrawn.An average of 51.4 percent of scar volume reduction was achieved after one session of intralesional cryosurgery treatment (average preoperative hypertrophic scars and keloids volume, 1.82 +/- 0.33; average posttreatment volume, 0.95 +/- 0.21; p < 0.0022). Significant alleviation of objective and subjective clinical symptoms was documented. Mild pain or discomfort during and after the procedure was easily managed. Only mild local edema and epidermolysis, followed by a short reepithelialization period, were evident. During the 18-month follow-up period, there was no evidence of bleeding, infection, adverse effects, recurrence, or permanent depigmentation. The histomorphometric analysis demonstrated rejuvenation of the treated scars (i.e., parallelization) and a more organized architecture of the collagen fibers compared with the pretreated scars. This study demonstrated the increased efficacy of this method as a result of increased freezing area of deep scar material compared with that obtained with contact/spray probes. As a result, fewer treatment cycles are needed. Because the reepithelialization period is short, treatment intervals, if any, can be shortened to 2 to 3 weeks. This intralesional cryoneedle method is simple to operate and safe to use, it necessitates less postoperative care of the wound, and it can easily be added to any preexisting cryosurgical unit.
5-FLUOROURACIL, INTRALESIONAL
Intralesional 5-fluorouracil in the treatment of keloids: an open clinical and histopathologic study. Kontochristopoulos G, Stefanaki C, Panagiotopoulos A, Stefanaki K, Argyrakos T, Petridis A, Katsambas A. Dermatology Department, Andreas Sygros Skin Hospital, Athens, Greece.	J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):474-9. Abstract quote   BACKGROUND: The treatment of keloids remains unsatisfactory. Intralesional 5-fluorouracil (FU) has not been much investigated as a monotherapy in the treatment of keloids. OBJECTIVE: We sought to evaluate the use of intralesional injections of 5-FU in the treatment of keloids. METHODS: A total of 20 patients (11 male and 9 female) were treated once weekly with intralesional injections of 5-FU (50 mg/mL). Patients received an average of 7 treatments. Average injection volumes were 0.2 to 0.4 mL/cm2. All patients had full blood cell count, liver function tests, and renal function tests before and after treatment was commenced. A total of 10 patients had biopsy specimens taken before starting treatment as a baseline and after 6 sessions. Routine hematoxylin-eosin and immunohistochemical analysis detecting Ki-67 and transforming growth factor-beta were performed on paraffin sections. All patients were followed up for 12 months, or until recurrence was noted. RESULTS: Of 20 patients, 17 (85%) showed more than 50% improvement. Only one did not respond favorably. Small and previously untreated lesions improved the most. Pain (20 of 20), hyperpigmentation (20 of 20), and tissue sloughing (6 of 20) were the main adverse effects. Histopathologic and immunohistochemical evaluation were consistent with the clinical observations. Ki-67 proliferative index was significantly reduced (P = .0001) after treatment. Transforming growth factor-beta was reduced less significantly. Recurrence was noted in 47% (9 of 19) of patients who responded to treatment within 1 year. A correlation was found ( P = .028) between the duration of the lesions and recurrence. CONCLUSION: Our study demonstrates that intralesional 5-FU may be effective in the treatment of keloids, but recurrence is common and further investigation is required.
LASER
Treatment Response of Keloidal and Hypertrophic Sternotomy Scars: Comparison Among Intralesional Corticosteroid, 5-Fluorouracil, and 585-nm Flashlamp-Pumped Pulsed-Dye Laser Treatments. Manuskiatti W, Fitzpatrick RE. Dermatology Associates and Cosmetic Laser Associates of San Diego County Inc, 9850 Genesee Ave, Suite 480, La Jolla, CA 92037.	Arch Dermatol 2002 Sep;138(9):1149-55 Abstract quote OBJECTIVE: To compare the clinical response of keloidal and hypertrophic scars after treatment with intralesional corticosteroid alone or combined with 5-fluorouracil (5-FU), 5-FU alone, and the 585-nm flashlamp-pumped pulsed-dye laser (PDL). DESIGN: Prospective, paired-comparison, randomized controlled trial. SETTING: A private ambulatory laser facility. PATIENTS: Ten patients with previously untreated keloidal or hypertrophic median sternotomy scars at least 6 months after surgery that were considered problematic by the patients. INTERVENTIONS: Five segments were randomly treated with 4 different regimens: (1) laser radiation with a 585-nm PDL (5 J/cm(2)); (2) intralesional triamcinolone acetonide (TAC) (20 mg/mL); (3) intralesional 5-FU (50 mg/mL); and (4) intralesional TAC (1 mg/mL) mixed with 5-FU (45 mg/mL). One segment of each scar received no treatment and served as a control. MAIN OUTCOME MEASURES: Scar height, erythema, and pliability were evaluated before and every 8 weeks after treatment. Patients' subjective evaluations were tabulated. Histologic sections of segments were examined in 1 biopsy sample per segment at week 32. RESULTS: There was a statistically significant clinical improvement in all treated segments. No significant difference in treatment outcome vs method of treatment was noted. However, intralesional formulas resulted in faster resolution than the PDL: scar induration responded better to intralesional formulas, scar texture responded better to the PDL, and scar erythema responded the same as the control with all treatments. Adverse sequelae, including hypopigmentation, telangiectasia, and skin atrophy, were observed in 50% (5/10) of the segments that received corticosteroid intralesionally alone. No long-term adverse sequelae were demonstrated in the segments treated with other modalities. CONCLUSIONS: Clinical improvement of keloidal and hypertrophic scars after treatment with intralesional corticosteroid alone or combined with 5-FU, 5-FU alone, and PDL seemed comparable, with the exceptions of the incidence of adverse reactions, which were most common with intralesional corticosteroid. Intralesional 5-FU is comparable to the other therapies.
Energy density and numbers of treatment affect response of keloidal and hypertrophic sternotomy scars to the 585-nm flashlamp-pumped pulsed-dye laser Woraphong Manuskiatti, MD Richard E. Fitzpatrick, MD Mitchel P. Goldman, MD La Jolla, California	J Am Acad Dermatol 2001;45:557-65 Abstract quote Background: The 585-nm flashlamp-pumped pulsed-dye laser (PDL) has proven to be the treatment of choice for certain keloids and hypertrophic scars, but the precise fluence, numbers of treatment, and treatment interval remain anecdotal. Objective: This study was performed to determine whether the therapeutic outcome of the PDL varies with the energy density (fluence) of the laser pulses and numbers of treatment. Method: Ten previously untreated, erythematous, keloidal or hypertrophic median sternotomy scars of 10 patients were divided into 4 segments and were randomly treated with a 585-nm PDL at a fluence of 3, 5, and 7 J/cm2 to 3 of 4 segments every 4 weeks for a total of 6 treatment sessions. One segment of each patient's scars was untreated and served as a control. Clinical improvement including scar height, erythema, and pliability was evaluated before treatment and every 8 weeks for a total period of 32 weeks. Self-assessment was also determined by patients on a 25% increment of improvement scale comparing week 0 and week 32. Results: A significant improvement in scar height, erythema, and pliability was noted in all laser-treated scar areas. There was no significant difference in treatment outcome versus the fluence of the laser (3, 5, and 7 J/cm2), although there was a trend for lower fluences to show more improvement. Objective clinical improvement was seen as early as week 16, after more than two treatments were given. Multiple treatments (>2) appeared to provide a greater percentage of scar resolution. Conclusions: The clinical improvement of scars after PDL treatment demonstrates no statistically significant fluence dependence in this study, but a trend toward better response with lower fluences is seen. In addition, multiple treatment sessions are suggested for achieving greater response.
RADIOTHERAPY
Treatment of keloids by surgical excision and immediate postoperative single-fraction radiotherapy. Ragoowansi R, Cornes PG, Moss AL, Glees JP. Department of Plastic and Reconstructive Surgery, St. George's Hospital, UK.	Plast Reconstr Surg. 2003 May;111(6):1853-9. Abstract quote   The authors report the outcomes of patients with keloid scars treated with a protocol of extralesional excision and immediate single-fraction adjuvant radiotherapy. The design of the study was a retrospective analysis with up to 5-year outcome data. The setting was a single treatment team, University Teaching Hospital in London, United Kingdom. Participants (n = 80) were treated for 80 keloid scars (59 percent female patients, 76 percent nonwhite), and 44 percent of keloids were located on earlobes. For all patients, prior treatment without radiotherapy had failed. The salvage treatment reported in this article is combined extralesional excision and immediate postoperative external-beam radiotherapy. A 10-Gy dose of superficial 60-kV or 100-kV photon irradiation was given within 24 hours of the operation. The main outcome measure was freedom from recurrence of keloid scars. Results were that all keloid scars were controlled at 4-week follow-up. Probability of relapse at 1 year was 9 percent; at 5 years, probability of relapse was 16 percent. The earlobe showed no greater chance of relapse than other sites on the body. The authors' report shows that extralesional excision of keloid followed by early, single-fraction, postoperative radiotherapy is both simple and effective in preventing recurrence at excision sites.
Ear-lobe keloids: treatment by a protocol of surgical excision and immediate postoperative adjuvant radiotherapy. Ragoowansi R, Cornes PG, Glees JP, Powell BW, Moss AL. Department of Plastic and Reconstructive Surgery, St George's Hospital, London, UK.	Br J Plast Surg 2001 Sep;54(6):504-8 Abstract quote There is no universally agreed policy for treating keloid scars of the ear lobe following piercing. We treated 35 patients (34 women) for high-risk ear-lobe keloids; the average age was 24 years (range: 16-44 years). All had failed to respond to prior treatment with massage and silicone, and corticosteroid injection. The keloids were excised extralesionally and the defects were closed with interrupted prolene sutures. The operative scar was covered with topical 2% lignocaine-0.25% chlorhexidine sterile lubricant gel under a transparent adhesive dressing. Adjuvant postoperative radiotherapy of 10 Gy, applied as 100 kV photons (4 mm high-voltage therapy (HVT) Al), was given within 24 h of surgery. All keloid scars were controlled at 4 weeks' follow-up. At 1 year, three out of 34 cases followed up had relapsed (probability of control: 91.2%). At 5 years, a further four out of the remaining 31 patients had relapsed (cumulative probability of control at 5 years: 79.4%). There were no cases of serious toxicity.
SILICONE GEL SHEETS
Silicone gel sheets relieve pain and pruritus with clinical improvement of keloid: possible target of mast cells. Eishi K, Bae SJ, Ogawa F, Hamasaki Y, Shimizu K, Katayama I. Department of Dermatology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan	J Dermatolog Treat. 2003 Dec;14(4):248-52. Abstract quote   Silicone gel sheet treatment is widely used to treat hypertrophic scars and keloids since it is easily applied and prevents scar pain and itching. We used Cica-Care silicone gel sheets in the conservative treatment of six patients for 24 weeks and recorded pain, itching, redness, and scar elevation every 4 weeks. We also investigated the number of mast cells and Fas antigen expression in the lesional skin (one patient) before and after treatment. The pain and itching clearly decreased after 4 weeks of the silicone gel sheeting and disappeared after 12 weeks. Twelve weeks were required for a reduction in scar redness and elevation. After 24 weeks, a decrease in the number of mast cells and the enhanced expression of Fas antigen by lesional fibroblasts were observed. Thus, silicone gel sheeting is effective and safe, especially with more severe symptoms of pain and itching possibly induced by mediators derived from increased mast cells.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

Pathologists Who Make A Difference
Search for a Physician Specialist

Last Updated December 7, 2006

Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.

Copyright © The Doctor's Doctor