Effects of moisturization on epidermal homeostasis and differentiation.

Moisturizers are commonly used for routine skin care. This study assessed the effects of a moisturizer on barrier function, epidermal architecture, keratinocyte proliferation, and physiological regulation of the epidermis in photoaged but otherwise normal skin. Fifteen women with moderately photoaged forearms were treated twice a day for 4 weeks with a moisturizer containing dimethicone and glycerine. Baseline and post-treatment transepidermal water loss (TEWL) and ipsilateral forearm biopsies were obtained. Epidermal thickness, melanin levels, keratinocyte proliferation, and expression of keratins were evaluated. Induction of keratins 6 and 16, commonly associated with keratinocyte proliferation and wound healing, was observed. Epidermal thickness increased by 0.019 mm (P = 0.005), barrier function improved (TEWL decreased by 13%) and melanin intensity decreased (P = 0.004). Even nonxerotic, photoaged skin may appear younger, benefiting structurally and functionally from routine use of moisturizers containing dimethicone and glycerine.

In vivo model of histologic changes after treatment with the superpulsed CO(2) laser, erbium:YAG laser, and blended lasers: a 4- to 6-month prospective histologic and clinical study.

BACKGROUND AND OBJECTIVE: To compare the in vivo histologic effects of the pulsed carbon dioxide (CO(2)) and erbium:ytrium aluminum garnet (Er:YAG) lasers and to assess the effects of combining CO(2) and Er:YAG laser modalities during a single treatment session. We previously reported 10 patients treated with four laser regimens: CO(2) alone, CO(2)/Er:YAG, Er:YAG alone, Er:YAG/CO(2) with time points at 1 hour and 7 days between laser treatment and histologic analysis. This study found that the optimal treatment consisted of limited CO(2) laser passes followed by Er:YAG. This treatment produced less collagen injury, less thermal necrosis, and more robust epithelial and dermal fibrous tissue regeneration in the acute phase of healing. The present study examines the histologic changes resulting from the host healing response to laser treatment on long-term follow-up of 4-6 months. STUDY DESIGN/MATERIALS AND METHODS: The Stanford University Committee on Human Subjects in Medical Research approved this study. Nine patients with actinic damage and indications for rhytidectomy volunteered for this interventional study in which each patient served as both experimental and control. The right preauricular area was treated at five sites with the following: (1) CO(2), (2) CO(2) followed by Er:YAG, (3) Er:YAG, (4) blended CO(2)/Er:YAG (Derma-Ktrade mark), (5) phenol. Each was subjected to full-face or sub-unit treatment. Each patient was followed up initially daily then weekly for healing of the full-face laser and for differences in healing of the five treatment areas. Five patients were selected for histologic evaluation. At 4-6 months, these patients underwent rhytidectomy with immediate removal of laser-treated skin, which was evaluated histologically by the study dermatopathologist, who was blinded to the treatment at each site. RESULTS: CO(2) laser treatment produced the greatest thickness of neocollagen (0.27 mm; P < 0.05), the highest neocollagen density (P < 0.05), the greatest decrease in elastosis (27%), but took the longest time for healing and resolution of erythema and inflammation (up to 6 months). Er:YAG used alone produced the least collagen density, with the thinnest band of neocollagen (0.08 mm), but the most rapid resolution of erythema and inflammation (within 10 days). Combined CO(2)/Er:YAG treatments, including Derma-Ktrade mark and CO(2) followed by Er:YAG produced histologic changes that were intermediate, as well as recovery that was intermediate (resolution of erythema within 1 month); the development of neocollagen was greater in CO(2)-containing modalities than Er:YAG used alone by a statistically significant margin (P = 0.001). These histologic findings were corroborated by clinical correlation by examination of the five treatment spots in nine patients and in full-face treatments in 100 patients. CONCLUSION: Collagenesis is greatest with CO(2) and least with Er:YAG. Elastosis decreased to the greatest degree with CO(2), least with erbium, and to an intermediate extent with blended CO(2)/Er:YAG regimens (sequential and Derma-K). These changes from control are statistically significant with all regimens (P < 0.05). Blended CO(2)/Er:YAG treatments provide an optimal combination of the benefits of CO(2) but with lesser erythema and healing delay. Clinical and histologic findings change over time for different treatments. Thus, long-term histology is critical for predicting results of treatment.

Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts.

Extracellular matrix hyaluronan is prominent during wound healing, appearing at elevated levels early in the repair process. It is prevalent throughout the course of fetal wound healing, which is scar-free, but decreases late in adult wound repair, that is often marked by scarring. To determine whether aberrant hyaluronan metabolism is associated with the excessive scarring that characterizes keloids, cultured fibroblasts derived from keloids and from the dermis of normal human skin and scar were compared. Levels of hyaluronan in 48 h conditioned media of keloid-derived cultures were significantly lower than in cultures of normal skin and scar fibroblasts. Profiles of hyaluronan polymer size were comparable in these two cell types, suggesting that excessive hyaluronan degradation was not involved. Hydrocortisone decreased hyaluronan levels approximately 70% in the conditioned media of both keloid and normal fibroblasts. Diminished hyaluronan accumulation in keloid-derived cells compared with normal fibroblasts was also observed in an in vitro wound healing model. Histolocalization of hyaluronan in keloids, normal skin, and scar samples confirmed the biochemical observations that the dermis of keloids, which comprises most of the scar tissue, contained markedly diminished levels of hyaluronan. Alterations in hyaluronan in the epidermis overlying keloids, however, were also observed. A modest increase in hyaluronan staining intensity was observed in the epidermis of keloids, as well as changes in the patterns of distribution within the epidermis, compared with that in normal skin and scar. Increased hyaluronan was present in the granular and spinous layers of the keloid epidermis Abnormalities are present apparently in both the overlying epidermis as well as in the dermis of keloids. Aberrations in signaling between keloid stroma and keloid epidermis may underlie abnormalities that contribute to the excessive fibrosis characteristic of these lesions.

Basal cell carcinoma with tumor epithelial and stromal giant cells: a variant of pleomorphic basal cell carcinoma.

A case of basal cell carcinoma with giant cells of the central epithelial and surrounding stromal components is presented. The lesion was an 8-mm dome-shaped papule on the ear of a 66-year-old man. The giant cells of the epithelial component shared the immunophenotype of the more typical cells of the basal cell carcinoma (keratin, smooth muscle actin, and bcl-2 positive), whereas the stromal giant cells were positive only for bcl-2. This case represents a peculiar variant of pleomorphic basal cell carcinoma, the significance of which is unknown.

Histologic analysis of the thermal effect on epidermal and dermal structures following treatment with the superpulsed CO2 laser and the erbium: YAG laser: an in vivo study.

BACKGROUND AND OBJECTIVE: To compare the in vivo histologic effects of the carbon dioxide (CO2) and erbium:yttrium aluminum garnet (Er:YAG) lasers. To ascertain the effects of combining CO2 and Er:YAG laser modalities during a single treatment session. STUDY DESIGN/MATERIALS AND METHODS: Ten patients underwent laser treatment to four left preauricular sites 7 days prior to rhytidectomy as follows: CO2 alone, CO2/Er:YAG, Er:YAG alone, and Er:YAG/CO2. The right preauricular area was identically treated 1 hour prior to rhytidectomy. Laser treated skin was excised during rhytidectomy and was evaluated histopathologically in a blinded manner. RESULTS: After 7 days, all groups were reepithelialized and showed equal neo-collagen formation. After 7 days, CO2/Er:YAG and Er:YAG alone had the least collagen injury and thickest epidermis and papillary dermis of all groups. Specimens lased 1 hour prior to excision showed the least collagen injury and thermal necrosis when treated with CO2/Er:YAG and Er:YAG alone. Four passes with CO2 removed 250 microm of tissue, while eight passes with the Er:YAG removed 160 microm of tissue. CONCLUSIONS: Limiting CO2 laser passes and ending with Er:YAG produces less collagen injury, less thermal necrosis, and more robust epithelial and dermal fibrous tissue regeneration. CO2 followed by Er:YAG has similar thermal necrosis and collagen injury as Er:YAG alone, presumably due to Er:YAG removal of CO2 induced thermal injury.

The validity of ex vivo laser skin treatment for histological analysis. A prospective controlled study.

BACKGROUND: Laser treatment of skin following removal from human subjects has been the staple of laser research. However, no study has been done to assess the efficacy of ex vivo skin for predicting the behavior of laser treatments in living human tissue. OBJECTIVE: To assess the validity of the ex vivo model by comparing histological characteristics of skin treated with laser prior to and following its removal in rhytidectomy. STUDY DESIGN: Nonrandomized controlled intervention study in which each patient served as both experimental subject and control for different skin sites. PATIENTS: Ten patients with actinic skin changes. INTERVENTIONS: Patients underwent laser treatment to 4 left preauricular sites 1 hour prior to rhytidectomy as follows: carbon dioxide laser treatment alone, carbon dioxide laser treatment followed by erbium:YAG laser treatment, erbium:YAG laser treatment alone, and erbium:YAG laser treatment followed by carbon dioxide laser treatment. The skin was examined by a dermatopathologist blinded to the identity of each specimen. Untreated skin was also removed and immediately subjected to laser treatment identical to that employed in the in vivo skin. This skin was examined histologically. MAIN OUTCOME MEASURES: Regularity of ablation, depth of the necrotic zone, amount of skin removed, degree of collagen injury, and degree of inflammation. RESULTS: There were significant differences between the ex vivo and in vivo groups. The ex vivo specimens demonstrated more than 10 times the irregularity of ablation of the in vivo specimens (irregularity index of 3.0 for the ex vivo group vs 0.25 for the in vivo specimens; P < .05). The incidence of collagen injury was slightly lower for the ex vivo group (1.0 vs 1.3), as was the degree of inflammation (1.4 vs 1.5). The greatest differences were the significantly smaller necrotic zone in the ex vivo specimens (51 vs 71 microns) and the smaller amount of skin removed (118 vs 234 microns). These findings were consistent for all 4 laser treatment regimens studied. CONCLUSIONS: Significant differences were found between the in vivo and ex vivo models. Irregularity of ablation in the ex vivo specimens was 10 times that in the living specimens, limiting histological accuracy in the ex vivo model. The ex vivo skin model underestimated the amount of tissue ablation. This suggests that an in vivo model should be adopted as the standard for laser research.

Infiltrative basal cell carcinoma occurring in sites of biopsy-proven nodular basal cell carcinoma.

Over 200 basal cell carcinomas (BCCs) are biopsied and subsequently excised each year at the Veterans Affairs Palo Alto Health Care System (VAPAHCS). A focal infiltrative pattern developed in the region of the biopsy scar in the re-excision specimens of 20 cases out of approximately 400 BCCs (< 5%) examined histopathologically over a 2-year period. The patient population included predominantly male, elderly Caucasians (mean age 71), and all tumors fulfilled clinical and histologic criteria for nodular BCC at the time of initial punch or shave biopsy. No patient showed recurrence of tumor following simple re-excision with 2-3 mm surgical margins, with a mean follow up of 25.4 months after excisional surgery. These neoplasms had a more benign clinical course, possibly related to scar formation in healing sites of previously biopsied nodular BCC, rather than true aggressive-growth BCC. The authors conclude that a focal infiltrative pattern in a re-excision specimen may occur histologically as a scar-induced pattern which mimics an aggressive-growth BCC, but does not appear to have the same prognosis. We believe this is an important histologic observation, as recognition of biopsy scar changes in an excisional specimen of BCC may help to distinguish it from true aggressive-growth BCC.

Desmoplastic and spindle-cell malignant melanoma. An immunohistochemical study.

The clinical, histologic, and immunohistologic features of 22 desmoplastic melanomas (DMM), 10 mixed desmoplastic and spindle-cell melanomas (DMM/SMM), and two cellular spindle-cell melanomas (SMM) were studied. Patients ranged in age from 35 to 91 years (mean, 67) and included 23 men and 11 women. Seventeen cases occurred in sun-damaged skin of the head and neck. 11 were on the extremities, and six on the trunk. Except for two cases, all were Clark's level IV or V. Twenty-two (65%) cases were associated with a recognizable overlying pigmented lesion. Thirty of 32 (94%) DMM and DMM/SMM were clearly positive for S100. S100 staining was limited to < 5% of the spindle cells in two DMM/SMM. All DMM were negative when stained with HMB45. Three DMM/ SMM were immunoreactive with HMB45, as were both SMM. CD68 staining was limited to < 5% of the spindle cells in two of 32 DMM and DMM/SMM and 20% of the cells in one of two SMM. Nine (32%) DMM and DMM/SMM contained significant numbers of spindle cells immunoreactive for SMA but not desmin. In five cases, the number of actin-positive spindle cells. Two color stains for SMA and S100 demonstrated that these smooth-muscle actin positive cells constituted a separate spindle-cell population, consistent with reactive myofibroblasts. This study indicates that the immunohistologic features of desmoplastic melanoma differ from those of conventional melanoma. If a problematic spindle-cell skin lesion is a suspected melanocytic process, HMB45 is unlikely to provide confirmatory (or exclusionary) evidence for the diagnosis of DMM. Similarly, because of the variability in S100 expression in this neoplasm, the absence of S100 staining should not be relied on too heavily to exclude DMM if the clinical and histologic features favor that diagnosis. Caution should be exercised in the interpretation of numerous actin-positive spindle cells in isolation of additional confirmatory or exclusionary data as desmoplastic melanomas may contain significant numbers of these cells.

Increased proportion of aggressive-growth basal cell carcinoma in the Veterans Affairs population of Palo Alto, California.

BACKGROUND: We have noted a high frequency of aggressive-growth basal cell carcinomas (BCCS) in our patient population. Subtypes observed with increased frequency include morpheaform, infiltrative, and micronodular. OBJECTIVE: Our purpose was to examine the frequency of histologic subtypes of all BCCs seen in the dermatology clinics in the Veterans Affairs Palo Alto Health Care System in an 18-month period. METHODS: We reviewed 432 consecutive primary BCC biopsy specimens taken from 252 patients. RESULTS: Aggressive-growth BCC was observed in 20.7% of biopsy specimens, including 13.4% morpheaform, 5.7% infiltrative, and 1.6% micronodular subtypes. The mean age of the patient population was 70 years, with a standard deviation of 9.1 years. CONCLUSION: Our observed percentage of aggressive-growth BCC is substantially higher than in most other large studies. A high frequency of aggressive-growth BCC coupled with the increasing incidence of nonmelanoma skin cancer may have significant implications for future health care resource allocation.

Benign lymphangioendothelioma.

We describe a 40-year-old white man with a red-brown, indurated plaque on the proximal aspect of his right thigh. The lesion had been present since birth, and the patient had a 20-year clinical history of recurrent cellulitis in the same area. The histopathologic features of the lesion included permeation of the dermis by flattened, endothelium-lined channels without cellular atypia, hemorrhage, or inflammation. The endothelial cells were stained intensely with monoclonal antibody anti-CD34 (clone MY10). In addition, antibodies to factor VIII antigen, HLA-DR, smooth muscle actin, ICAM-1, and the lectin Ulex europaeus labeled the luminal cells. The basement membrane of the channels stained with anti-type IV collagen and laminin. Desmin-positive cells were abundant adjacent to the channels. Factor XIIIa stained both mononuclear cells and occasional dendritic cells in the perivascular area. Ki-67 immunolabeling could not be demonstrated on fresh or frozen tissue. Electron microscopy revealed the presence of both tight junctions and a well-formed, continuous basement membrane but the absence of Weibel-Palade bodies.

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a high incidence of colon cancer. Dysplasia is a precursor to carcinoma and a predictor of malignant potential; epithelia containing high-grade or severe dysplasia is most likely to develop cancer. The cellular oncogene c-src and its viral homologue v-src (the transforming gene of Rous sarcoma virus) encode 60-kD cytoplasmic, membrane-associated protein tyrosine kinases. For the viral protein or transforming mutants of the cellular protein (Src), a close correlation exists between elevated tyrosine kinase activity and malignant transformation of cells. Previously, we and others observed elevated Src activity in sporadic colon carcinomas and benign adenomas at greatest risk for developing cancer (those with large size, villous architecture, and/or severe dysplasia). Here we report that Src activity and protein abundance are also elevated in neoplastic UC epithelia. Activity is highest in malignant and severely dysplastic epithelia, and 6-10-fold higher in mildly dysplastic than in nondysplastic epithelia. Thus, Src activity is elevated in premalignant UC epithelia, which is at greatest risk for developing cancer. The data suggest that activation of the src proto-oncogene is an early event in the genesis of UC colon cancer.

Desmoplastic neurotropic malignant melanoma.

Desmoplastic neurotropic malignant melanoma is a rare spindle cell variant of malignant melanoma. This chapter reviews its clinical presentation; histologic, immunohistochemical, and ultrastructural features; differential diagnosis; and critical therapeutic issues.

Caterpillar bodies: distinctive, basement membrane-containing structures in blisters of porphyria.

In a previous study, we reported on the observation of a relatively specific, linear body in the roofs of bullae from cases of porphyria cutanea tarda. In the present study, we expand on these observations to show the presence of these bodies in lesions of pseudoporphyria cutanea tarda and erythropoietic protoporphyria. Furthermore, we have applied immunoperoxidase techniques using antibodies to type IV collagen and laminin to show that they are composed of basement membrane material. Because the segmented, elongated shapes of these bodies reminded us of the larvae of butterflies, we coined the term "caterpillar bodies" to describe them. These bodies are similar in their composition to the Kamino bodies of Spitz's nevi, cylindrical bodies in adenoid cystic carcinoma, Civatte bodies of lichen planus, and the collagenous spherules seen in a number of conditions, and may provide a unique clue to the diagnosis of the porphyric bullous eruptions.

Dysplastic nevi can be diagnosed and graded reproducibly: a longitudinal study.

BACKGROUND: Poor interobserver reproducibility in diagnosing and grading dysplastic melanocytic nevi is often cited as evidence against the ability of pathologists to recognize such an entity. OBJECTIVE: We attempted to examine the diagnostic profiles of melanocytic lesions of two dermatopathologists in a stable population base. METHODS: All 2600 melanocytic neoplasms were diagnosed at Stanford University Medical Center during the past 4 years by one dermatopathologist from 1987 to 1989 and a different dermatopathologist in 1990 and 1991. The two independently evaluated these lesions unaware of the other's criteria. RESULTS: The diagnostic profile of the two pathologists shows a striking degree of similarity: 76.7% versus 75.3% of all nevi were diagnosed as acquired melanocytic nevi, 8.8% versus 12.0% were diagnosed as mildly dysplastic, 7.0% versus 6.8% as moderately dysplastic, and 2.7% versus 1.6% as severely dysplastic. CONCLUSION: Our findings suggest that the two pathologists are using reproducible criteria for diagnosing and grading dysplastic nevi.

Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction.

An association between erythema multiforme and herpes simplex virus infection has been supported by clinical studies and by the detection by immunofluorescence of herpes viral antigen in sera and skin biopsy specimens of patients with erythema multiforme. In rare cases, the virus has also been isolated in cultures of skin biopsy specimens of erythema multiforme. To investigate further the association between erythema multiforme and herpes simplex virus, we used the polymerase chain reaction for herpes simplex virus to examine skin lesions from patients with erythema multiforme. In this study herpes simplex virus DNA was detected in 11 of 31 biopsy specimens of erythema multiforme; six additional cases showed equivocal amplification results, which is suggestive of low amounts of viral DNA. Seven skin and mucosal biopsy specimens with the histologic changes of herpes virus infection served as positive controls: all were positive for herpes simplex virus DNA. Viral DNA was not detected in control biopsy specimens from skin excised for unrelated conditions. These studies support the association of herpes simplex virus in the pathogenesis of some cases of erythema multiforme. The polymerase chain reaction provides a quick and effective method of detecting herpes simplex virus in lesions of herpes-associated erythema multiforme. Furthermore, the polymerase chain reaction may delineate those cases of erythema multiforme that are etiologically related to herpes virus infection and therefore might be treated with acyclovir to prevent recurrence.

Bacillary angiomatosis. The histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease.

Cutaneous vascular proliferations that clinically or pathologically resemble Kaposi's sarcoma, pyogenic granuloma, or histiocytoid (epithelioid) hemangioma may occur in patients with human immunodeficiency virus infection. These lesions, which respond well to antibiotic therapy, harbor bacilli similar to the agent of cat scratch disease. We evaluated 21 biopsy specimens from 13 patients with this condition, which we have called "bacillary angiomatosis." The architecture resembled that of lobular capillary hemangioma (pyogenic granuloma), but the endothelial cells were often larger, polygonal, and sometimes markedly atypical. The presence of neutrophils, leukocytoclastic debris, and granular material (bacteria), and the absence of either spindled cells, bizarrely shaped vascular channels, or hyaline globules help to distinguish bacillary angiomatosis from Kaposi's sarcoma. By electron microscopy, the protuberant endothelial cells were different from those of histiocytoid hemangiomas in that aggregates of intermediate filaments were absent, while numerous Weibel-Palade bodies were present. The immunophenotype of the endothelial cells was distinct from that of Kaposi's sarcoma; almost all cells showed both Factor VIII RAg and Ulex europaeus lectin positivity. Enzyme histochemistry also showed a pattern distinct from Kaposi's sarcoma. Bacillary angiomatosis presents a unique constellation of clinical and microscopic findings. It is important to be aware of these characteristics, because these lesions are easily treatable with antibiotic therapy.

Cutaneous vascular lesions and disseminated cat-scratch disease in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

Cutaneous lesions develop frequently in patients infected with human immunodeficiency virus (HIV). We describe the clinical features of four patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex who developed angiomatous nodules involving skin and bone, 2 of whom were scratched by a cat. Some of these lesions were clinically indistinguishable from Kaposi sarcoma. When examined with Warthin-Starry staining and electron microscopy, these nodules were noted to contain numerous clumps of a bacterium. Immunoperoxidase staining with an antiserum raised against the cat-scratch disease bacillus stained these organisms in all patients. Cat-scratch disease is usually a self-limited infection, but complicated or prolonged infections have been described in both normal and immunocompromised hosts. In our patients infected with HIV, manifestations of systemic cat-scratch disease included angiomatous nodules, severe systemic symptoms of fever, chills, night sweats and weight loss, elevated erythrocyte sedimentation rate, and decreased hematocrit. Cutaneous lesions involved the face, trunk, and extremities and numbered 2 to greater than 60; osseous lesions involved the fibula, radius, femur, and tibia, and were present in two of four patients. Treatment with x-ray therapy, intralesional vinblastine, penicillin, dicloxacillin, cephradine, and nafcillin had no effect on any lesions; however, treatment with erythromycin, doxycycline, or antimycobacterial antibiotics resulted in complete and rapid resolution of the cutaneous and osseous lesions, and the accompanying signs and symptoms of systemic infection. In patients with AIDS or AIDS-related complex, angiomatous nodules should be carefully evaluated for the presence of this organism, which can be treated and cured with antibiotic agents.

Epithelioid haemangioma-like vascular proliferation in AIDS: manifestation of cat scratch disease bacillus infection?

Papular and nodular skin lesions that clinically resembled Kaposi sarcoma, but histologically showed a distinct epithelioid haemangioma-like appearance, were noted in seven patients with the acquired immunodeficiency syndrome. Clusters of bacteria that had the structure of gram-negative rods were identified within each of the vascular proliferations by electron microscopy. The bacteria did not stain with the Brown-Brenn, acid-fast, or other histochemical stains for infectious organisms, but did stain with Warthin-Starry--ie, the staining profile was that described for the cat scratch disease (CSD) bacillus. Immunoperoxidase staining, using antisera raised in rabbits against cultured CSD bacillus, showed a positive reaction with the bacterium in all five cases tested. The two surviving patients have both given histories of having been scratched by a cat. In several patients, the vascular lesions regressed after therapy with antibiotics appropriate for CSD bacillus infection.