The effects of systemic diseases, genetic disorders and lifestyle on keloids.

Keloid are a fibroproliferative disorder caused by abnormal healing of skin, specifically reticular dermis, when subjected to pathological or inflammatory scars demonstrating redness, elevation above the skin surface, extension beyond the original wound margins and resulting in an unappealing cosmetic appearance. The severity of keloids and risk of developing keloids scars are subjected to elevation by other contributing factors such as systemic diseases, general health conditions, genetic disorders, lifestyle and natural environment. In particular, recently, daily physical work interpreted into mechanical force as well as the interplay between mechanical factors such as stress, strain and stiffness have been reported to strongly modulate the cellular behaviour of keloid formation, affect their location and shape in keloids. Herein, we review the extensive literature on the effects of these factors on keloids and the contributing predisposing mechanisms. Early understanding of these participating factors and their effects in developing keloids may raise the patient awareness in preventing keloids incidence and controlling its severity. Moreover, further studies into their association with keloids as well as considering strategies to control such factors may help clinicians to prevent keloids and widen the therapeutic options.

The HEDGEHOG-GLI1 pathway is important for fibroproliferative properties in keloids and as a candidate therapeutic target.

Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing that can negatively impact patient quality of life. The lack of animal models has limited research on pathogenesis or developing effective treatments, and the etiology of keloids remains unknown. Here, we found that the characteristics of stem-like cells from keloid lesions and the surrounding dermis differ from those of normal skin. Furthermore, the HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem-like cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, the HH signal inhibitor vismodegib reduced keloid reconstituted tumor size and keloid-related gene expression in nude mice and the collagen bundle and expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic targets of keloids.

A Case of Axillary Fibroadenoma That Grew Rapidly from Axillary Accessory Breast Tissue over 40 Days.

Axillary accessory breast (AAB) occurs in 2%-6% of women. Like normal breast tissue, ABB can undergo changes, including periodic enlargement that can result in a palpable axillary mass. Fibroadenoma is the most common benign subcutaneous tumor of the breast: it occurs in approximately 25% of women and accounts for 50% of all breast biopsies. However, fibroadenoma in AAB is rare (2.6%). Here, we describe the case of a patient who was diagnosed first with left AAB on the basis of clinical and magnetic imaging resonance findings, and then 40 days later with fibroadenoma in left AAB by histopathology of the resected mass. The tumor, which had been undetectable at the initial visit, had transformed into a clinically obvious, hard, protruding mass at surgery. Thus, fibroadenomas originating from AAB can grow quickly, and imaging-based diagnosis should be confirmed with histology. Treatment should involve complete excision of the fibroadenoma and surrounding AAB.

A Case of Takotsubo Cardiomyopathy after Dermal Burn on the Face and Hands.

Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy or broken heart syndrome, generally has a good prognosis but occasionally causes serious complications. It is often triggered by physical and emotional stressors. Burns have been associated with takotsubo cardiomyopathy in six cases in the literature. We report here the seventh case. The patient, an 86-year-old woman with burn injuries to her face and hands due to a fire in her home, developed takotsubo cardiomyopathy. The condition was suspected soon after presentation due to precautionary electrocardiogram and then laboratory findings of elevated myocardial biomarkers. The diagnosis was then confirmed by left ventriculography. The cardiomyopathy resolved spontaneously without complications. The burn in our patient affected only 5% of total body surface area, but its impact may have been augmented by emotional stress caused by the patient losing her home in the fire. Our review of the six burn-related takotsubo cardiomyopathy cases in the literature showed that two of the cases also had small burns in combination with severe emotional stress. Since all six cases developed serious complications, the possibility of takotsubo cardiomyopathy should be suspected, even with small burns.

Keloidal Collagen May Be Produced Directly by αSMA-positive Cells: Morphological Analysis and Protein Shotgun Analysis.

Keloids are fibroproliferative lesions caused by abnormal dermal wound healing. Keloidal collagen (KC) is a pathognomic feature of keloids, but the mechanism by which it forms is unknown. This study aimed to evaluate the histopathology of KC and thereby gain clues into how it forms. Methods: The cross-sectional study cohort consisted of a convenience series of patients with keloids who underwent surgical excision. Skin pieces (3 mm2) were collected from the keloid center and nearby control skin. Histopathology was conducted with light and electron microscopy and immunohistochemistry. KC composition was analyzed with protein shotgun analysis. Results: Microscopic analyses revealed the ubiquitous close association between KC and αSMA-positive spindle-shaped cells that closely resembled myofibroblasts. Neither KC nor the spindle-shaped cells were observed in the control tissues. Compared with control skin, the collagen fibers in the KC were overall thinner, their diameter varied more, and their spacing was irregular. These features were particularly pronounced in the collagens in the vicinity of the spindle-shaped cells. Protein shotgun analysis did not reveal a specific collagen in KC but showed abnormally high abundance of collagens I, III, VI, XII, and XIV. Conclusions: These findings suggest that KC may be produced directly by myofibroblasts rather than simply being denatured collagen fibers. Because collagens VI and XII associate with myofibroblast differentiation, and collagen XIV associates with local mechanical stress, these collagens may reflect, and perhaps contribute to, the keloid-specific local conditions that lead to the formation of KC.

Hemodynamics and Vascular Histology of Keloid Tissues and Anatomy of Nearby Blood Vessels.

Keloids are red' invasive scars that are driven by chronic inflammation in the reticular dermis. The role of blood vessels in keloid behavior remains poorly understood. In the present study with 32 keloid patients, we examined the hemodynamics of keloid tissue, the anatomy of the blood vessels feeding and draining the keloids, and the vascular histology of keloids. Methods: Ten patients with large anterior chest keloids underwent near-infrared spectroscopy, which measured regional saturation of oxygen and total hemoglobin index in the keloid and surrounding skin. Another 10 patients with large chest keloids and three healthy volunteers underwent multidetector-low computed tomography. The extirpated chest keloids of 12 patients were subjected to histology with optical, CD31 immunohistochemical, and electron microscopy. Results: All keloids had a low regional saturation of oxygen and a high total hemoglobin index, which is indicative of blood congestion. Multidetector-low computed tomography revealed dilation of the arteries and veins that were respectively feeding and draining the keloid leading edge. Hematoxylin-eosin staining and CD31 immunohistochemisty revealed considerable neovascularization in the keloid leading edge but not in the center. Electron microscopy showed that the lumens of many vessels in the keloid center appeared to be occluded or narrowed. Conclusions: Keloids seem to be congested because of increased neovascularization and arterial inflow at the leading edge and blocked outflow due to vascular destruction in the center. The surrounding veins seem to expand in response to this congested state. Methods that improve the blood circulation in keloids may be effective therapies.

Secondary Cutaneous Ossification in Keloids of the Lower Abdomen: A Report of Two Cases.

Cutaneous ossification is a rare benign dermatological condition in which bone forms in the dermis or subcutaneous tissue. It is classified as primary when it emerges without a pre-existing condition and secondary when it is associated with an underlying condition such as trauma, scars, inflammation, or neoplastic disease. The secondary form accounts for most cases of cutaneous ossification. The pathogenesis of cutaneous ossification is not clear. Keloids are benign fibroproliferative skin disorders characterized by chronic inflammation. Their pathogenesis is also not fully understood. We report two cases of postoperative secondary ossification in lower abdominal keloids and review the literature on secondary ossification of the skin. We speculate that severe chronic inflammation in keloids drives osteoblastic transformation of mesenchymal stem cells, endothelial cells, or fibroblasts in the keloids.

A Case of Scapular Hidradenoma Treated as a Keloid.

Hidradenomas are relatively rare benign tumors in the dermis that differentiate into eccrine or apocrine sweat glands. They often present as round or oval nodules and vary in color. Generally, they occur in the head and neck region. Keloid scars are often red, elevated lesions that are caused by chronic inflammation in the reticular dermis. These scars demonstrate a preference for high skin-tension sites, including the scapular region. Herein, we describe a case of a dark red hidradenoma on the scapular region with a high incidence of acne surrounding the lesion area that was initially diagnosed as an acne-initiated keloid. However, local steroid injection did not cure the lesion. After excision, histopathology revealed typical findings for hidradenoma, namely mucinous, polygonal, and clear cell composition. In some cases, as presented it may be challenging for clinicians to differentiate between hidradenoma and keloid due to the similar clinical features. Thus, hidradenoma should be taken in consideration as a differential diagnosis when encountering steroid-refractory keloid-like lesions. Moreover, early biopsy or surgical resection should be considered.

The Latest Strategy for Keloid and Hypertrophic Scar Prevention and Treatment: The Nippon Medical School (NMS) Protocol.

In 2006, we established a scar/keloid-specialized unit in the Department of Plastic, Reconstructive, and Aesthetic Surgery at Nippon Medical School (NMS) in Tokyo, Japan. In the ensuing 15 years, we treated approximately 2,000 new scar/keloid patients annually. This extensive experience has greatly improved the efficacy of the treatments we offer. Therefore, we discuss here the latest NMS protocol for preventing and treating keloids and hypertrophic scars. While this protocol was optimized for Japanese patients, our experience with a growing body of non-Japanese patients suggests that it is also effective in other ethnicities. The extensive evidence-based experience underlying the NMS protocol suggests that it may be suitable as the foundation of a standard international prevention/treatment algorithm for pathological scars.

Combination Therapy Composed of Surgery, Postoperative Radiotherapy, and Wound Self-management for Umbilical Keloids.

BACKGROUND: A universally accepted therapeutic strategy for umbilical keloids has not been determined. Our team has had considerable success with combination therapy composed of surgical excision followed by postoperative radiotherapy and steroid plaster/injection. METHODS: All consecutive patients with umbilical keloids that developed from endoscopic surgical scars and underwent minimal-margin keloid excision followed by umbilicoplasty with a flap if needed, tension-reduction suturing, and postoperative radiotherapy in 2013-2017 in the keloid/scar-specialized clinic at the Department of Plastic, Reconstructive and Aesthetic Surgery of Nippon Medical School. The postsurgical radiotherapy regimen was 15 Gy administered in 2 fractions over 2 consecutive days. Radiotherapy was followed by tension-reducing wound self-management with silicone tape or, if needed, steroid plaster. The primary study focus was keloid recurrence during the 24-month follow-up period. Recurrence was defined as the growth of stiff red lesions in even small areas of the scar that was refractory to 2-6 months of steroid-plaster therapy. RESULTS: The case series consisted of 34 patients with 34 lesions. Three lesions (8.8%) recurred. One recurrence was successfully treated by concomitant steroid plaster/injection. The other 2 cases were resistant to steroid injection and underwent reoperation without radiotherapy followed by 6 months of steroid-plaster therapy. None of the 3 cases recurred within 2 years of steroid plaster/injection completion or reoperation. CONCLUSION: Umbilical keloids can be successfully treated by customized treatment plans that involve appropriate surgical modalities (including umbilicoplasty, if required), postoperative radiotherapy (15 Gy/2 fractions/2 days), and wound/scar self-management with silicone tape and steroid plaster.

Photodynamic Therapy Delays Cutaneous Wound Healing in Mice.

BACKGROUND: Cutaneous wound healing is a complex, dynamic physiological process. Traditional methods of promoting wound healing are not always effective. Consequently, alternative modalities, such as photodynamic therapy (PDT), are needed. We examined the effectiveness and underlying mechanisms of PDT in a murine model of acute wound healing. METHODS: Two excisional wounds were produced, one on each side of the midline, in C57bL/6J mice. Methyl 5-aminolevulinate hydrochloride (MAL) was applied to the right-side wound. After 1 to 3 hours of incubation, the wound was irradiated with red light. The left-side wound was not treated with MAL or red light. On Day 14, the wounds were excised and subjected to histological and immunohistochemical analysis. RESULTS: During the first week, no difference was seen between the two sides. However, at week 2, PDT-treated wounds exhibited delayed re-epithelialization. On Day 14, hematoxylin and eosin (HE) staining showed a continuous epithelial lining in untreated wounds. In contrast, PDT-treated wounds partially lacked epithelium in the wound bed. Masson's Trichrome (MTC) staining showed a thicker dermis and more collagen fibers and inflammatory cells in PDT-treated wounds than in untreated wounds. Immunohistochemical analyses showed significantly fewer CD31+ blood vessels and greater collagen III density in PDT-treated wounds than in untreated wounds. However, treated and untreated wounds did not differ in collagen I density. CONCLUSIONS: PDT delayed acute wound healing in a murine model of secondary intention wound healing.

Photodynamic therapy for keloids and hypertrophic scars: a review.

PURPOSE: Keloid is a poorly understood disease that is unique to humans. Hypertrophic scars are similar to keloids and may transform into keloids over time. The standard treatments for these scars are limited by inconsistent efficacy and long treatment/follow-up times. Therefore, a new treatment that is effective for all abnormal scar cases is needed. One option may be photodynamic therapy (PDT). This review assesses the current evidence regarding the safety and efficacy of PDT for keloids and hypertrophic scars. METHODS: PubMed, Medline and Web of Science were searched from 1900 onwards for the following terms: 'keloid and photodynamic therapy (PDT)'; 'hypertrophic scar and photodynamic therapy (PDT)'; and 'scar and photodynamic therapy (PDT)'. Articles were included if they reported using topical PDT to treat keloids or hypertrophic scars, the patient(s) had one or more keloids and/or hypertrophic scars, and the effect of PDT on these abnormal scars was described. RESULTS: In total, 538 articles were identified. Thirteen fulfilled all inclusion criteria. Eight were laboratory studies on keloid/hypertrophic scar explants, fibroblasts or tissue-engineered skin models and five were clinical studies/case reports. The clinical results of PDT on keloids and hypertrophic scars are encouraging. CONCLUSION: PDT appears to play a promising role in keloid and hypertrophic scar therapy but additional clinical studies, particularly randomised clinical trials, are needed.

Surgical excision and postoperative radiotherapy for keloids.

Keloids can be treated in a number of ways, including by surgery. Multiple studies now show that while surgical monotherapy associates with extremely high rates of recurrence (50%-80%), postoperative radiotherapy can significantly reduce these recurrence rates. Ongoing improvements in radiation technology have further increased the safety and efficacy of this combination protocol. Of the various radiotherapies that have been used in this setting, electron beam (ß-ray) irradiation is currently the best due to its excellent dose distribution and safety. The maximal biologically effective dose (BED) for keloids is 30 Gy (using an estimated α / ß ratio of 10); increasing the dose has no further benefits and elevates side effects. Over the last two decades, we have modified and then fine-tuned our radiotherapy protocol for keloid excision wounds. Thus, our early protocol was used for all body sites and consisted of 15 Gy/3 fr/3 days. We then customised the radiotherapy protocol so that body sites that are highly prone to recurrence (e.g. the anterior chest) receive higher doses while low recurrence sites like the earlobe receive a much smaller dose. More recently, we tweaked this body site-customised protocol so that fewer fractions are employed. Therefore, we currently apply 18 Gy/3 fr/3 days to high-recurrence sites, 8 Gy/1 fr/1 day to earlobes and 15 Gy/2 fr/2 days to other body sites. These radiotherapy protocol changes were accompanied by the evolution of body site-customised surgical approaches. As a result of these developments, our overall keloid recurrence rate is now below 10%.

Diagnosis and Treatment of Keloids and Hypertrophic Scars-Japan Scar Workshop Consensus Document 2018.

There has been a long-standing need for guidelines on the diagnosis and treatment of keloids and hypertrophic scars that are based on an understanding of the pathomechanisms that underlie these skin fibrotic diseases. This is particularly true for clinicians who deal with Asian and African patients because these ethnicities are highly prone to these diseases. By contrast, Caucasians are less likely to develop keloids and hypertrophic scars, and if they do, the scars tend not to be severe. This ethnic disparity also means that countries vary in terms of their differential diagnostic algorithms. The lack of clear treatment guidelines also means that primary care physicians are currently applying a hotchpotch of treatments, with uneven outcomes. To overcome these issues, the Japan Scar Workshop (JSW) has created a tool that allows clinicians to objectively diagnose and distinguish between keloids, hypertrophic scars, and mature scars. This tool is called the JSW Scar Scale (JSS) and it involves scoring the risk factors of the individual patients and the affected areas. The tool is simple and easy to use. As a result, even physicians who are not accustomed to keloids and hypertrophic scars can easily diagnose them and judge their severity. The JSW has also established a committee that, in cooperation with outside experts in various fields, has prepared a Consensus Document on keloid and hypertrophic scar treatment guidelines. These guidelines are simple and will allow even inexperienced clinicians to choose the most appropriate treatment strategy. The Consensus Document is provided in this article. It describes (1) the diagnostic algorithm for pathological scars and how to differentiate them from clinically similar benign and malignant tumors, (2) the general treatment algorithms for keloids and hypertrophic scars at different medical facilities, (3) the rationale behind each treatment for keloids and hypertrophic scars, and (4) the body site-specific treatment protocols for these scars. We believe that this Consensus Document will be helpful for physicians from all over the world who treat keloids and hypertrophic scars.

Z-plasty and Postoperative Radiotherapy for Upper-arm Keloids: An Analysis of 38 Patients.

Therapies for upper arm keloids include surgical excision followed by postoperative radiotherapy, silicone tape stabilization, and steroid plaster. However, a universally accepted therapeutic strategy for upper-arm keloids is lacking. METHODS: All consecutive patients with single upper-arm keloids who underwent keloid excision followed by tension-reducing suturing, multiple z-plasties, and postoperative radiotherapy in 2013-2016 in the keloid/scar specialist clinic at the Department of Plastic, Reconstructive and Aesthetic Surgery of Nippon Medical School, were included in this case series study. Only keloids that arose from the small injury produced during Bacillus Calmette-Guérin vaccination were selected. The postsurgical radiotherapy regimen was 18 Gy administered in 3 fractions over 3 days. Radiotherapy was followed by tension-reducing wound self-management with silicone tape and, if needed, steroid plaster. The primary study objective was keloid recurrence during the 24-month follow-up period. Recurrence was defined as the growth of stiff red lesions in even small areas of the scar that was refractory to at least 2 months of steroid plaster therapy. RESULTS: In total, 38 patients with 38 lesions were enrolled. Two lesions (5.3%) recurred. Both recurrences were successfully treated by concomitant steroid plaster and steroid injection. The recurrence patients were significantly more likely than the nonrecurrence patients to have multiple keloids. The 2 groups did not differ in terms of original keloid size. CONCLUSIONS: Upper-arm keloids can be successfully treated by customized plans that involve appropriate surgical modalities (including multiple z-plasties), postoperative radiotherapy (18 Gy/3 fractions/3 d), and postoperative wound/scar self-management with silicone tape and steroid plaster.

Two Cases of Granular Cell Tumors that Clinically Mimicked Hypertrophic Scars and Keloids.

We report two cases of granular cell tumors (GCTs) arising on rare sites, namely, the nape and umbilicus. While GCTs have a very characteristic histology, their clinical signs and symptoms are non-specific. Therefore, it is extremely difficult to make a diagnosis of GCT on the basis of clinical findings only. The two cases reported here were clinically similar to hypertrophic scars and keloids, respectively. Skin surgeons should remember that GCTs are an important differential diagnosis from hypertrophic scars and keloids.

Two Cases of Sclerotic Fibroma of the Skin that Mimicked Keloids Clinically.

Sclerotic fibromas of the skin (SFSs) have a very characteristic histology but the clinical signs are non-specific. Consequently, it is extremely difficult to make a diagnosis of SFS on the basis of the clinical findings only. We report here two cases of SFS arising on the right scapular region and the right lower leg, respectively. Both cases were clinically similar to keloids. Skin surgeons should remember that SFSs are an important differential diagnosis from keloids.

Pyoderma Gangrenosum Secondary to Severe Congenital Neutropenia.

We encountered a case of a man who was diagnosed with severe congenital neutropenia as a child and presented at the age of 45 years with pyoderma gangrenosum (PG) of the lower leg. PG associates with an underlying systemic disease, most commonly inflammatory bowel, rheumatic, or hematological disease or malignancy. However, in many cases, the underlying disease was not known. Surgery can trigger PG. The histopathological features of PG were nonspecific, and diagnosis requires excluding other conditions that have a similar appearance. Our analyses showed that the PG in our case was secondary to severe congenital neutropenia, which had promoted an infection of keratinous cysts. The patient bore a mutation in the ELANE gene encoding neutrophil elastase. Only 1 other case of neutropenia-associated PG has been reported previously: the association was only suspected. The present complex case was effectively treated by systemic treatment of the neutropenia with granulocyte colony-stimulating factor and regional surgical treatment. Histology of the excised tissue revealed keratinous cysts that were diffusely distributed with inflammatory granulation tissue. We believe that the rupture of the walls of the keratinous cysts may have caused the PG. At the time of writing (3 years since the initial presentation), the PG has not recurred. This case shows the importance of performing detailed examinations, including blood tests, to determine the disease underlying PG. This was because if the underlying disease was identified, its treatment was likely to promote healing of the wound after local surgery and prevent recurrence.

Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target.

BACKGROUND: Keloid is a fibroproliferative skin disorder that is characterized by collagen accumulation and blood vessel proliferation in the reticular layer of the dermis. It is caused by prolonged inflammation after cutaneous injury. Several studies suggested recently that epithelial mesenchymal transition (EMT) is involved in the development of fibrosis. This study assessed whether EMT also participates in keloid development and/or aggravation. METHODS: Resected keloid (n = 19) and normal skin (n = 13) samples were subjected to immunohistochemical, immunofluorescent, and Western blot analyses of their expression of epidermal (E-cadherin) and mesenchymal (vimentin) proteins. RESULTS: Immunohistochemical analysis showed that the keloid tissues had more vimentin-positive cells in the epidermis than the normal tissues. When normal primary keratinocytes were cultured with proinflammatory cytokines, the cobblestone-shaped cells changed to a spindle shape and many vimentin-positive cells were detected. When immortalized HaCaT keratinocytes were cocultured in split-well plates with normal or keloid-derived fibroblasts, they also underwent EMT, as indicated by their greater vimentin expression on Western blot analysis compared with HaCaT cells that were cultured alone. CONCLUSIONS: EMT was observed in keloid specimens. EMT was induced by inflammatory cytokines and fibroblasts. EMT may be involved in keloid generation and/or aggravation and may have potential as a keloid treatment target.

Pott's Puffy Tumor in an Adult: A Case Report and Review of Literature.

Pott's puffy tumor is a subperiosteal abscess of the frontal bone with osteomyelitis which has become rare because of the widespread use of antibiotics. Here, we report a case of Pott's puffy tumor in a 46-year-old man who visited the department of dermatology with painful swelling of the forehead. Despite open drainage and oral antibiotic therapy, the symptoms recurred twice in the following month. Computed tomography revealed a fistula of frontal bone. The eventual diagnosis was Pott's puffy tumor. The patient underwent endoscopic surgery at the department of otorhinolaryngology and achieved a complete recovery.