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.

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.

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.

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.

Histologic features in primary cutaneous squamous cell carcinomas in immunocompromised patients focusing on organ transplant patients.

BACKGROUND: In organ transplant recipients (OTR) there is an increased incidence of cutaneous squamous cell carcinomas (CSCC), and they may be aggressive. OBJECTIVE: We wanted to determine whether any histologic features were characteristic or more common in CSCC of OTR. METHODS: A total of 518 immunocompetent individuals with 601 primary CSCC were examined. Seventy-nine OTR with 231 primary CSCC, 53 renal OTR, 25 heart/heart lung OTR, and 1 liver OTR were examined. RESULTS: In all patient populations, CSCC occurred dominantly in chronically sun-exposed skin. In OTR, however, a greater percentage occurred on the extremity, particularly the upper extremity, and they occurred at an earlier age. Features that were significantly more common in OTR were acantholytic changes, early dermal invasion, an infiltrative growth pattern with or without desmoplasia, and Bowen's disease with carcinoma. In OTR primary CSCC were also significantly deeper at time of diagnosis. CONCLUSIONS: Our findings confirmed the association of ultraviolet radiation exposure with development of CSCC in OTR. The increased depth of the primary CSCC in OTR is surprising because these patients are followed closely for skin cancer compared with immunocompetent patients. The other morphologic features that were significantly more common in OTR may theoretically reflect not only the type of iatrogenic immunosuppression in these patients, but also other procarcinogenic effects of their medications.

Delayed cutaneous reactions to heparin in antiphospholipid syndrome during pregnancy.

BACKGROUND: Clinical symptoms related to antiphospholipid antibodies often first occur during pregnancy with the diagnosis of antiphospholipid syndrome (APS). Unfractionated heparin (UFH) and low-dose aspirin are considered as first-line treatments for pregnant women with APS and recurrent fetal loss. However, in addition to an increased incidence of hemorrhagic side-effects and thrombocytopenia there are a number of drug eruptions with cutaneous components secondary to the use of UFH. One of these eruptions has been classified as a delayed type I.V. hypersensitivity reactions at the sites of UFH injections. The majority of these reactions occur in pregnant women. METHOD: We present three pregnant patients who developed delayed hypersensitivity reactions at the sites of UFH injections. Two patients had documented APS and the other patient had two previous spontaneous abortions. RESULTS: The histopathologic and immunohistochemical findings in the biopsy specimens from the sites of the delayed reactions were distinctive. The inflammatory infiltrate contained CD3+ and CD4+ lymphoid cells with plasma cells, and eosinophils. There was a marked increased in mast cells with increased stromal cells within the dermis and increased vascular proliferation. CONCLUSIONS: The distinctive histopathologic and immunohistochemical features seen in the delayed hypersensitivity reactions at the sites of UFH injections may be modulated by the immunomodulatory effects of UFH as well as the hormonal levels and cytokine patterns during pregnancy. Alternative therapies may not always be successful in resolving the reactions.

Benign ectopic thyroid tissue in a cutaneous location: a case report and review.

BACKGROUND: For many years, lateral, aberrant thyroid tissue in adults was a term used almost exclusively for metastatic thyroid carcinoma. However, aberrant, benign ectopic thyroid tissue does occur, and it is most commonly found as a part of the evaluation of endocrine dysfunction. Rarely, aberrant, benign ectopic thyroid presents as a primary mass. CASE REPORT: We present a 35-year-old female who presented for removal of a lifelong posterior lateral neck nodule. RESULTS: Histologic examination and immunohistochemical studies confirmed the presence of aberrant, benign ectopic thyroid tissue. The patient had no endocrine problems, and she had a normally located and functioning thyroid gland. CONCLUSIONS: This case illustrates that not all aberrant thyroid tissues in adults are malignant or associated with endocrine disorders. This case also illustrates the rare association of ectopic thyroid and a normally located and functioning thyroid gland. In this patient, a somatic mutation in a transcription factor important in thyroid migration could explain these findings.

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.

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.

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.

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.

An unusual dematiaceous fungal infection of the skin caused by Fonsecaea pedrosoi: a case report and review of the literature.

BACKGROUND: A case of an unusual dematiaceous fungal infection of the skin in a 43-year-old man with diabetes mellitus treated with steroids for reactive airway disease is presented. He developed chromoblastomycosis in the left wrist and was treated with antifungals and multiple surgical excisions. RESULTS: Histologic examination of the excised tissue revealed widespread suppurative granulomatous inflammation in the dermis and subcutaneous tissue. Thick-walled internally septated brown fungal cells were found both inside multinucleated giant cells and extracellularly. Non-to-lightly pigmented septate hyphal elements, however, were also identified with special stains and, in retrospect, on one of the routinely stained sections. In culture, the organism was reported to initially grow as soft white colonies that soon turned to black and velvety. CONCLUSIONS: The two unusual features of this case include the controversial report of the organism's initial growth in culture as soft white colonies and the presence of hyphal elements in addition to the sclerotic bodies in the dermis and subcutaneous tissue. This has not been reported before in human cases of dermal infection by Fonsecaea pedrosoi.