Leflunomide: an immune modulating drug that may have a role in controlling secondary infections with review of its mechanisms of action.

BACKGROUND: Leflunomide (LEF) is an immune modulator used most commonly for rheumatoid arthritis (RA). The mechanisms of action of LEF also include anti-microbial effects, particularly anti-viral effects. OBSERVATIONS: We present three patients with atopic dermatitis on azathioprine therapy who had multiple verrucae and in two molluscum contagiosum (MC) that were resistant to repeated conventional therapies. These patients were switched to LEF, and all the patients showed complete resolution of their verrucae and MC within 2 months of starting therapy. In addition, all three patients showed equivalent to better control of their atopic dermatitis with LEF. CONCLUSIONS: LEF has previously been reported to be a useful immune modulator for the treatment of severe atopic dermatitis. The spectrum of anti-viral effects previously seen with leflunomide did appear beneficial in these patients in clearing verrucae and MC, which had been resistant to conventional therapies while the patients were on azathioprine.

Eruptive keratoacanthoma-type squamous cell carcinomas in patients taking sorafenib for the treatment of solid tumors.

BACKGROUND: Protein kinases (PKs) are indispensable for most cellular processes, and deregulation of PKs can lead to activation of oncogenic and anti-apoptotic pathways and immune dysregulation. OBJECTIVE: To report the development of keratoacanthoma (KA)-type squamous cell carcinomas (SCCs) in patients treated with the multikinase inhibitor sorafenib for the treatment of solid tumors, to present the possible mechanisms for induction of these SCCs, and to discuss the implications for discontinuation of therapy and possible cotherapies to decrease this side effect. PARTICIPANTS: Fifteen patients taking the multikinase inhibitor sorafenib for the treatment of solid tumors who developed multiple KA-type SCCs, which continued to develop while the patients were undergoing therapy but stopped with discontinuation of sorafenib. LIMITATIONS: This report is limited because it is a retrospective study that included only patients who developed multiple KA-type SCCs. CONCLUSIONS: Development of cutaneous SCCs appears to be a side effect limited to sorafenib, a multikinase inhibitor that inhibits not only multiple tyrosine kinases (TKs), but also the serine-threonine kinase Raf. The incidence of cutaneous SCCs does not appear greater with multikinase inhibitors that inhibit only TKs.

Dermatofibrosarcoma protuberans and giant cell fibroblastoma exhibit CD99 positivity.

According to most authors, dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) represent the adult and juvenile forms, respectively, of the same disease entity, as evidenced by similar morphology, an identical chromosomal translocation, and CD34 positivity. It has been shown that DFSP and nuchal-type fibroma (NTF) (which is also CD34-positive) are related lesions, and that there might possibly be a continuum between the two. In addition, NTF exhibits CD99 positivity. It was therefore, hypothesized that both DFSP and GCF would show similar immunopositivity for CD99. Archives of pathology at several institutions were searched for DFSP and GCF tissue blocks. A total of 29 DFSP and 5 GCF were analyzed by immunohistochemistry for expression of CD99. Twenty-three of 29 DFSP (79%) and 2 of 5 GCP (40%) expressed CD99. Comparison of CD99 and CD34 showed that the non-tumoral periphery of DFSP was less probable to be CD99 positive, but this finding was not statistically significant.

Polycystic ovary syndrome (PCOS) with melanocytic mucosal macules: the role of STK11 gene polymorphisms in PCOS and Peutz-Jeghers syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex genetic disorder that is the most common endocrinopathy that affects women. OBSERVATIONS: We report two individuals with PCOS with a genetic polymorphism in serine threonine kinase 11 (STK11). Both these individuals developed mucosal pigmentation suggesting Peutz-Jeghers syndrome (PJS), which is associated with mutations in STK11. Both individuals showed some improvement in their metabolic and endocrine dysregulation with therapies commonly used for PCOS. However, they continued to show progression of mucosa pigmentation. CONCLUSIONS: This is the first report of clinical overlap in individuals with PCOS and PJS, even though some individuals with PCOS show a polymorphism in STK11, which is the gene mutated in PJS. The importance of this clinical association is not clear but may be significant because of the association of STK11 dysregulation and the development of internal tumors.

Unexplained hypereosinophilia and the need for cytogenetic and molecular genetic analyses.

BACKGROUND: Idiopathic hypereosinophilic syndrome (HES) is a diagnosis made after the exclusion of other causes of eosinophilia. However, differentiation of idiopathic HES from eosinophilic leukemia is sometimes difficult. In some cases, these diagnoses can be differentiated by cytogenetic or molecular findings, as illustrated in the patients described herein. OBSERVATIONS: We describe 3 patients with HES and associated pruritus; 1 patient also had recurrent lesions of eosinophilic cellulitis. All 3 patients were initially diagnosed as having idiopathic HES, but after evaluation and demonstration of molecular abnormalities, they were classified as having eosinophilic leukemia. CONCLUSIONS: Patients with a diagnosis of idiopathic HES should be evaluated for cytogenetic or molecular genetic abnormalities. These abnormalities can establish a diagnosis of chronic eosinophilic leukemia and may provide clues for emerging therapies.

Molluscum contagiosum: recent advances in pathogenic mechanisms, and new therapies.

Two poxviruses, Molluscum contagiosum virus (MCV) and Variola virus are specific to humans. MCV is present worldwide and is directly passed by direct skin to skin contact to produce cutaneous and, rarely, mucosal lesions. It occurs predominantly in preadolescent children, sexually active adults, participants in sports with skin to skin contact, and in individuals with impaired cellular immunity. MCV characteristically proliferates within the follicular epithelium, and with routine fixation produces an area of retraction artifact separating layers 1 to 3 of CD34+ stromal cells that immediately surround the follicle from the surrounding dermis. This feature may be obscured when the lesions are inflamed, usually after rupture into the surrounding dermis. MCV is a cytoplasmically replicating virus. MCV-infected cells grow in size, while internal organelles are dislocated and eventually obliterated by a large intracytoplasmic inclusion. Rupture and discharge of the virus-packed cells occurs in a process similar to membrane debris and MCV accumulate in the crater-like ostium; MCV infection is spread by contact with infectious debris. In HIV-1-positive patients the histologic features, as well as the clinical features, may be atypical in patients with MCV infections. Not only are the lesions often large, but they may be verrucous and markedly hyperkeratotic. Recent sequencing of the MCV genome has increased our understanding and investigations into its mechanisms for avoiding host defense mechanisms. These include regions which encode for homologues of cellular chemokines and chemokine-binding proteins, a homolog of MHC1 and a viral FLICE-like inhibitory protein. Treatment, until recently, has depended upon tissue destruction including curettage, cryotherapy, CO(2) laser, electrodesiccation, trichloracetic acid and cantharadin. Recently, topical immune modulators have been used with some success. Understanding of the MCV genome is providing the basis for the development of drugs for therapy and prevention of MCV infections.

The imidazoquinolines and their place in the therapy of cutaneous disease.

The imidazoquinolines arose from efforts to develop a nucleoside analogue. Although molecularly similar to nucleosides, the imidazoquinolines did not have nucleoside-like activity. However, the imidazoquinolines induced immune modulatory cytokines, in part, because of their ability to activate toll receptors (TLR)s. Imiquimod, the first FDA-approved imidazoquinoline, has been marketed as a 5% cream, which is approved for the therapy of genital warts. The advantage of imiquimod therapy over other therapies for genital warts is the decrease in recurrence rate with the establishment of an adaptive immunological response or immunological memory/surveillance response. As tumours and viral infections are handled similarly by the immune system, there has been great interest in the use of topical imiquimod for the treatment of cutaneous neoplasms, particularly non-melanoma skin cancers. Future efforts in imidazoquinoline research is focused around the development of analogues with modifications in the immunological profiles, potency and penetration parameters that better focus these new analogues for the therapy of specific intracellular infections and neoplasms, as well as the development of imidazoquinolines for conditions related either directly or indirectly to patterns of immune dysregulation.

Squamous cell carcinomas arising from adnexal ductal cysts.

Malignant tumors arising from adnexal cysts are rare. We report 2 cases of squamous cell carcinomas that developed within cystic structures arising from adnexal ducts. An in situ hybridization technique for human papillomaviruses (HPV)-6/11, -16, -18, and -31, and immunohistochemical staining for p53 were performed. Both tumors showed focal expression of HPV-16 within areas showing squamoid changes and diffuse expression of p53 within the areas of invasive squamous cell carcinoma. Although nuclear staining for HPV has been identified in tumors of adnexal origin, to our knowledge these are the first cases in which a highly oncogenic HPV subtype, HPV-16, has been identified within squamous cell carcinomas arising from adnexal ductal structures. These cases may help explain primary cutaneous squamous cell carcinomas with no epidermal origin.

Chemical warfare agents: their past and continuing threat and evolving therapies. Part II of II.

Chemical warfare agents are ideal weapons for terrorists and for use in military operations against both civilian populations and troops. Thus, there have been efforts by the United States in cooperation with other concerned nations to develop animal models to understand the pathophysiology of the injuries induced by these agents, and to develop suitable animal models for testing of pre-and post-exposure protectants and therapies. Sulfur mustard remains the most significant chemical warfare agent that produces cutaneous injuries. Institution of standard recommendations prior to threatened exposure or after exposure are something that we need to be aware of in the world we live in. In addition, pre-and post-exposure therapies now being studied offer hope for moderating the mortality and morbidity that can result from chemical exposure.

Chemical warfare agents: their past and continuing threat and evolving therapies. Part I of II.

Chemical warfare agents are potentially accessible to even underdeveloped nations because they are easily and inexpensively produced. This means that they are ideal for use by terrorists and in military operations against civilian populations and troops. In terms of cutaneous injury, vesicants-mainly sulfur mustard-are the most significant chemical warfare agents. Advances in understanding the pathophysiology of the lesions produced by sulfur mustard have led to the research and development of barrier creams as well as pre- and post-exposure therapies to moderate the damage and accelerate healing. Part I of this paper will discuss the history and classification of chemical agents; Part II, which will appear in the September/October 2003 issue of SKINmed, will discuss characteristic manifestations of exposure to chemical agents, as well as prevention and therapy.

Nuclear expression of the antiapoptotic protein survivin in malignant melanoma.

BACKGROUND: Expression of the antiapoptotic protein survivin has been demonstrated in some melanocytic lesions and is believed to be required for melanoma cell viability. However, its diagnostic value in differentiating melanomas from nevi has not yet been examined. METHODS: Tissue microarray blocks were constructed with paraffin-fixed tissue of 19 nevi, 18 dysplastic nevi, 24 malignant melanomas, and 31 metastatic melanomas. Sections were then reacted with three antisurvivin antibodies (two monoclonal and one polyclonal) assessing labeling intensity (absent or weak, and moderate to strong) as well as the percentage of cells labeled (< 25%, > or = 25%). RESULTS: Of the antibodies evaluated, the polyclonal one was found to be the most sensitive. Nuclear immunoreactivity for survivin (i.e., > or = 25% of cells exhibiting and/or at least moderately intense staining) was seen in a subset of melanomas but not in nevi or dysplastic nevi (P < 0.05). CONCLUSIONS: Survivin is variably expressed in the cytoplasm in the entire spectrum of melanocytic lesions, with nuclear expression detectable only in melanomas. These data may underscore the importance of nuclear survivin in progression to melanoma and may prove useful in the differential diagnosis of melanoma versus nevus.

Hair follicle nevus in a distribution following Blaskho's lines.

We present a case of a rare follicular hamartoma, a hair follicle nevus. Although most previous reports have been solitary lesions, the case we are reporting had multiple papules and nodules following Blaskho's lines. There have been no reports of malignancies arising in these hamartomas.

Arachidonic acid-derived bioactive lipids: their role and the role for their inhibitors in dermatology.

BACKGROUND: In addition to corticosteroids, there are increasing numbers of anti-inflammatory agents that specifically target bioactive lipids generated from arachidonic acid. Knowledge of the diverse mechanisms of action of these different bioactive lipids holds promise in the therapy of a wide spectrum of cutaneous and systemic disorders. OBJECTIVE: Therapeutic manipulations of these lipid molecules through inhibition, stimulation, or direct replacement have broad physiologic effects. These therapeutic strategies not only modulate inflammation, pain, and hemostatic parameters, they also play a role in cardiac, respiratory, renal, and gastrointestinal function and disease, as well as in angiogenesis and in factors that control cell growth and apoptosis important in carcinogenesis. CONCLUSION: Newer drug discovery methods, including combinatorial chemistry with molecular modeling, have made it possible to develop inhibitors and analogs with increasing specificity and bioactivity and decreasing toxicity. Although the application of these analogs and inhibitors for cutaneous disease is limited today, either as primary agents or adjuvant therapy, these drugs will have a place in our therapeutic regimes of the future. We present a review of the therapeutic agents now available from manipulation of these bioactive lipids, and their role and future in dermatology.

Basaloid follicular hamartomas associated with autoimmune disease: a possible role for retinoids in therapy.

A basaloid follicular hamartoma (BFH) may be localized or diffuse. It may also be congenital or acquired. Development of diffuse BFHs has been associated with autoimmune disease and with the development of diffuse alopecia. Two women with autoimmune diseases had diffuse alopecia develop. We present the histologic features of BFH seen in these 2 women using vertical and transverse sections, and the response of 1 patient to retinoid therapy. Histologic sections showed a hamartomatous proliferation of hair follicles involving the majority of their hairs. The hamartomatous follicles showed variable degrees of hair differentiation. One patient, treated with oral and then topical retinoids, showed a partial regrowth of scalp hair and some regression of the cutaneous nodules. Increased sonic hedgehog signaling pathways with increased Gli-1 transcription has been shown to be present in the spectrum of follicular hamartomatous changes seen in BFHs. This may explain the response of one patient to retinoid therapy, because retinoids decrease Gli-1 transcriptional activity.

Treatment of disseminated granuloma annulare with a 5-lipoxygenase inhibitor and vitamin E.

Histologically, granuloma annulare (GA) is a common non-infectious necrobiotic granulomatous reaction pattern that correlates with a number of different, but relatively specific clinical presentations. The cause or causes of GA are unknown: when localized, it is usually self-limiting, but it may be persistent when disseminated. We present three women who had had disseminated GA for more than 1 year. One patient had previously been treated with isotretinoin with no response. All three patients were treated with vitamin E 400 IU daily and zileuton 2400 mg daily. All responded within 3 months with complete clinical clearing. The anti-inflammatory and immune regulatory effects of vitamin E and zileuton may be an effective treatment in some patients with prolonged disseminated/generalized GA.

Histopathologic features seen with radiation recall or enhancement eruptions.

BACKGROUND: Although a radiation recall or enhancement eruption has been associated with a number of chemotherapeutic drugs, the histologic features have rarely been described. OBJECTIVE: Our goal was to define the histologic features of radiation recall and enhancement eruptions in order to better understand their pathogenesis. METHODS: We present ten patients on chemotherapeutic agents who developed erythematous maculopapular to psoriasiform eruptions often with associated follicular pustules. These eruptions occurred at the sites of prior or concurrent radiation therapy. RESULTS: The most common class of drugs inducing these reactions were antibiotic chemotherapeutic agents alone or in combination with other chemotherapeutic drugs. In addition to routine histology, in four patients immunohistochemical staining for p53 was performed at the sites of the eruptions after resolution and at noninvolved sites matched for ultraviolet radiation (UVR) exposure. Histologic features in patients receiving concurrent radiation therapy included epidermal dysplasia, keratinocytes showing features of necrosis, increased mitotic figures, and a mixed inflammatory infiltrate. At sites of prior radiation therapy, the biopsy specimens showed a similar spectrum of epidermal changes and, in some cases, psoriasiform dermatitis with clearing within cells in the upper layers of the epidermis. Additional dermal changes included dermal fibrosis, vasodilatation, and atypical fibroblasts. Moderate to marked solar elastosis was seen in the majority of biopsy specimens. Immunohistochemical studies after resolution showed only a modest increase in p53 staining in epidermal keratinocytes in 3 of 4 sites of recall and enhancement eruptions after resolution of the reactions compared to skin that was matched for similar UVR exposure. CONCLUSION: Cumulative direct DNA damage and oxidative stress are probably important in radiation recall and enhancement eruptions, and these changes may be modulated by underlying nutritional deficits. Cumulative p53 mutations may play some role but are probably not a major factor in these eruptions. Mitochondrial dysfunction, which is known to occur with prior and concurrent radiation and chemotherapy, may be important in these eruptions. In addition to improvements in general nutrition, topical or oral antioxidant therapy may be a potential therapy to avoid radiation enhancement and recall reactions

Development of histologic features of scleroderma in congenital lesions.

BACKGROUND: Localized scleroderma has been reported after radiation therapy, but has never been reported to occur at the site of a congenital lesion. CASE REPORT: We present two patients, both with family histories of autoimmune disease, who reported unilateral hypopigmented areas on the trunk since birth. The areas remained asymptomatic and grew with the patients until adulthood when the areas became indurated then firm and showed hyperpigmentation. HISTOLOGY: Histologically, both lesions showed features of localized scleroderma with diffuse sclerosis of collagen and loss of periadnexal fat. There was a perivascular lymphoplasmocytic infiltrate with occasional eosinophils extending into the subcutaneous fat predominantly along fat septae, and diffuse loss of CD34+ stromal cell populations within the lesions. CONCLUSION: We propose that somatic mutations affecting vessels may predispose to increased endothelial cell apoptosis. This could lead to the development of an autoimmune response in some individuals, and the areas of localized scleroderma may be markers of susceptibility to autoimmune disease.

Topical 5% imiquimod for the therapy of actinic cheilitis.

BACKGROUND: Tissue-destructive and more selective cytotoxic therapies are the main methods used to treat actinic cheilitis. A topical immune stimulant, 5% imiquimod cream, has recently been used for treatment of cutaneous epithelial malignancies including squamous cell carcinoma in situ and basal cell carcinoma. OBJECTIVE: Our aim was to review the results in patients who had been treated for actinic cheilitis with imiquimod cream. METHODS: A review identified 15 patients with biopsy-proven actinic cheilitis who had been treated with topical imiquimod 3 times weekly for 4 to 6 weeks. All patients with histories consistent with facial herpes simplex or documented prior facial herpes simplex eruptions were treated with oral valcyclovir, 1 g/d, during imiquimod therapy. RESULTS: All 15 patients showed clinical clearing of their actinic cheilitis at 4 weeks after discontinuation of the topical imiquimod. Sixty percent of the patients experienced a moderate to marked increased local reaction consisting of increased erythema, induration, and erosions or ulcerations, which in some cases continued through the period of therapy. CONCLUSION: Imiquimod appears to have a role in the treatment of actinic cheilitis. However, the dose and duration of therapy, as well as the long-term efficacy, need to be established; and local reactions are to be expected and may not improve during therapy.

Lichen planus associated with hepatitis C virus: no viral transcripts are found in the lichen planus, and effective therapy for hepatitis C virus does not clear lichen planus.

BACKGROUND: Although hepatitis C virus (HCV) was not discovered until 1989, it was recognized for many years that a viral agent was responsible for many cases of posttransfusion or parenterally transmitted hepatitis. Acute HCV is often relatively mild; however, 70% to 80% of patients with HCV go on to develop chronic liver disease during a prolonged period of up to 40 years, and up to 50% of them may remain relatively asymptomatic during that time. A number of associated cutaneous findings have been reported in up to 15% of these patients including lichen planus-like eruptions (LP). OBJECTIVE: We sought to determine whether viral transcripts were present within the skin of patients with HCV and LP, and if systemic virologic response to interferon alfa and ribavirin correlated with response of the LP. Materials and methods A total of 4 men and 1 woman all presented with cutaneous eruptions of LP, and 1 had oral LP lesions. Cutaneous biopsies were performed on all patients. All patients were found to have chronic HCV. In addition to pathologic examination, immunohistochemical stains for lymphoid markers and reverse-transcriptase polymerase chain reaction for HCV was performed on the biopsy specimens. All patients were treated with interferon alfa and ribavirin. RESULTS: In LP there were scattered eosinophils seen in biopsy specimens of 4 of the 5 patients. The lymphoid infiltrate contained predominantly CD3(+) T cells and scattered KP-1(+) mononuclear cells, without CD20(+) B cells. Approximately one fourth of the T cells failed to mark with CD4. Although all patients were seropositive for HCV RNA at the time of biopsy, we were unable to detect HCV RNA by reverse-transcription polymerase chain reaction in any of the patients. The patients' LP showed an inconsistent response to therapy. CONCLUSION: The virus was not found in the LP lesion using reverse-transcription polymerase chain reaction for HCV. Thus, LP appears to be related to the pattern of immune dysregulation induced by HCV, probably in a host with an underlying susceptibility for autoimmune disease. The combination of interferon alfa and ribavirin may be effective in clearing the virus, but viral response did not correlate with clearing of LP.