Rate of Immunohistochemistry Utilization in the Diagnosis of Cutaneous Melanocytic Lesions.

ABSTRACT: Melanocytic lesions represent a large portion of the workload in many laboratories. Although many melanocytic nevi can be confidently diagnosed based on routine hematoxylin and eosin light microscopy, ancillary testing is often warranted. Various immunohistochemical (IHC) stains are routinely used in the diagnosis of melanocytic lesions. Because melanocytic lesions are frequently encountered in skin specimens, the use of IHC is likely to represent a significant area of resource utilization in dermatopathology laboratories. Our study investigates the rate of IHC utilization in the diagnosis of melanocytic lesions in a high-volume, government-funded, not-for-profit laboratory. Of the 1230 cases of melanocytic lesions investigated, including benign as well as malignant entities, 300 cases involved the utilization of IHC. IHC was used in a larger percentage of melanomas than nevi and in a larger percentage of melanoma in situ cases than invasive melanomas. SOX10 was overwhelmingly the most frequently used IHC.

Nodular Colloid Milium of the Conjunctiva and Anterior Orbit.

Colloid milium is a rare deposition disorder with accumulation of a characteristic amorphous substance in both protected and sun-exposed areas depending upon the disease subtype. The patient was a 59-year-old woman who was referred for evaluation of a gelatinous-appearing mass in the inferior fornix of the right eye, extending from the medial to the lateral canthal region, and extending up onto the bulbar conjunctival surface and anterior lacrimal gland. Hematoxylin and eosin stain of an incisional biopsy showed deposits of an amorphous brightly eosinophilic material within the conjunctiva with scattered plasma cells at the periphery. There was no evidence of monoclonality, and a Congo red stain was negative. Based on histopathologic findings, a diagnosis of nodular orbital colloid milium was made. To our knowledge, the adult and nodular forms of colloid milium have not been previously described as occurring in the conjunctiva or anterior orbit.

Cutaneous lupus erythematosus of the eyelid as a mimic of squamous epithelial malignancies: a clinicopathologic study of 9 cases.

PURPOSE: To describe 9 cases of chronic cutaneous lupus of the eyelid, its potential similarities with squamous epithelial malignancies, and clinical and histopathologic features that assist in distinguishing lupus from epidermal neoplasia. METHODS: The authors identified and reviewed 9 cases of cutaneous lupus involving the eyelid at their institutions since 1991. Published cases of cutaneous lupus involving the eyelid were identified using Ovid MEDLINE and PubMed and references within the articles. RESULTS: The average patient age at presentation was 52 years old (range 33-89) with a female-to-male ratio of 8:1. The right lower eyelid was the most commonly affected location, with 44% of the cases occurring at this site. Lesions had been present on average for 2.5 years prior to presentation (range 2-60 months). Lesions were clinically heterogeneous, ranging from macules to crusted shallow ulcers. In 44% of cases, the preoperative clinical diagnosis was that of either squamous cell carcinoma or basal cell carcinoma. The patients thought to have a skin malignancy were 10 years older at presentation, more likely to be male, and more likely to have ulcerative lesions with rapid onset when compared with the other lupus patients. CONCLUSIONS: A subset of patients with lupus (particularly discoid lupus) involving the eyelid have clinical features mimicking patients with squamous epithelial malignancy. In cases such as these, biopsies are critical for establishing the diagnosis and pursuing appropriate therapeutic approaches.

Synchronous and metachronous malignant melanomas arising in a human immunodeficiency virus-positive patient after the commencement of highly active antiretroviral therapy treatment: a case report.

BACKGROUND: We present an unusual case of a patient who developed four melanomas within a few months of diagnosis with human immunodeficiency virus and commencement of highly active antiretroviral therapy therapy. The patient had no previous history of melanoma, and previous skin checks were normal. CASE PRESENTATION: A 50-year-old Caucasian male drainlayer with Fitzpatrick type 2 skin presented for a routine skin examination. He had been diagnosed with human immunodeficiency virus 4 months earlier and commenced on highly active antiretroviral therapy therapy. He was found to have three melanomas (melanoma in situ stage) on excision biopsies, and when he presented for wider excisions of these sites a few weeks later, another new melanoma in situ was found. He had no other medical history of note, and no symptoms to report. He is being followed up 3-monthly. CONCLUSIONS: This case of a human immunodeficiency virus-positive person presenting with four cutaneous melanomas-occurring in both synchronous and metachronous fashion within a 4-month period-is being presented both for its uniqueness and also to highlight the increased need for close skin surveillance in human immunodeficiency virus-positive patients.

Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates.

There are no non-hormonal male contraceptives currently on the market despite decades of efforts toward the development of "male pills". Here, we report that triptonide, a natural compound purified from the Chinese herb Tripterygium Wilfordii Hook F displays reversible male contraceptive effects in both mice and monkeys. Single daily oral doses of triptonide induces deformed sperm with minimal or no forward motility (close to 100% penetrance) and consequently male infertility in 3-4 and 5-6 weeks in mice and cynomolgus monkeys, respectively. Male fertility is regained in ~4-6 weeks after cessation of triptonide intake in both species. Either short- or long-term triptonide treatment causes no discernable systematic toxic side effects based on histological examination of vital organs in mice and hematological and serum biochemical analyses in monkeys. Triptonide appears to target junction plakoglobin and disrupts its interactions with SPEM1 during spermiogenesis. Our data further prove that targeting late spermiogenesis represents an effective strategy for developing non-hormonal male contraceptives.

Enantiomeric Identification of Pregabalin by GC-MS via Methylation and S-TPC Chiral Derivatization.

Pregabalin is a Schedule V controlled substance which is defined as the (S) enantiomer of 3-(aminomethyl)-5-methylhexanoic acid. It is used legitimately to treat neuropathy in patients with diabetes as well as for epilepsy and fibromyalgia. Pregabalin is an amino acid and an amphoteric compound, which makes it difficult to analyze using the conventional GC-MS instrumentation found in most forensic drug analysis laboratories. Problems associated with the traditional GC-MS analysis of pregabalin include selective solubility, ring closure to the corresponding lactam in the GC injection port and/or the MS transfer line and difficulty with chiral derivatization due to the presence of a carboxylic acid moiety. Here, we show that these challenges can be overcome by methylating (capping) the carboxylic acid portion of the pregabalin molecule and converting to the corresponding methyl ester. Once the methyl ester is synthesized, chiral derivatization at the amine can be achieved to identify the controlled (S) enantiomer of pregabalin via GC-MS.

Cutaneous lupus erythematosus simulating squamous neoplasia: the clinicopathologic conundrum and histopathologic pitfalls.

BACKGROUND: The clinical distribution and character of cutaneous lupus erythematosus lesions can simulate squamous neoplasms, leading physicians to submit a shave biopsy specimen with a differential diagnosis of squamous neoplasm. OBJECTIVE: Our aim was to describe histologic features of interface dermatitis that cause difficulty in distinguishing between cutaneous lupus erythematosus and squamous neoplasia in shave biopsy specimens and to identify distinguishing criteria. METHODS: Twenty-six biopsy specimens from 10 patients initially diagnosed with squamous neoplasia that ultimately proved to be cutaneous lupus erythematosus were identified. Comparisons were made of these to 38 control biopsies of chronic cutaneous lupus erythematosus and 34 control biopsies of keratoses/carcinomas without lupus. All biopsies were scored (0 or 1: absent or present) with respect to 11 histologic criteria. RESULTS: The criteria of perifollicular inflammation, follicular plugging, vacuolar interface change, compact orthokeratosis, and acrosyringeal inflammation were significantly more common in the lupus cases than in the keratoses/carcinomas controls. The mean lupus case score was 6.88, lupus control score 6.55, and keratoses/carcinomas control score 5.08. LIMITATIONS: A limited number of patients were studied. Microscopic observations and assumptions with inherent subjectivity were used in establishing the histologic scores. CONCLUSION: Use of the criteria presented, although not absolute, should alert one to the possibility of lupus in an atypical squamous proliferation, especially in suspected squamous neoplasms that worsen or recur after therapy.

Epstein-Barr virus-positive diffuse large B-cell lymphoma.

While the World Health Organization included Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) as a provisional entity of a lymphoma occurring in older individuals without any known immunodeficiency in 2008, it has since been recognized that this entity may occur in younger individuals. As a result, the 2016 revision has substituted the modifier "elderly" with "not otherwise specified" (NOS). The NOS highlights that there are more specific entities with neoplastic EBV-positive large B cells such as lymphomatoid granulomatosis. Diagnosis requires that there be no other cause of immunodeficiency and that other more specific entities with neoplastic EBV plus large B cells be excluded. We present the case of an 81-year-old woman hospitalized for generalized weakness, increasing confusion, unexplained weight loss, and intermittent fevers. Examination showed lymphadenopathy, lesions in the liver and small intestine, and a very high EBV viral load. She experienced a rapid demise and at autopsy was found to have EBV+ DLBCL, NOS.

Cognitive effects of atypical antipsychotics in patients with Alzheimer's disease and comorbid psychiatric or behavioral problems: a retrospective study.

BACKGROUND: In addition to cognitive decline, 30% to 40% of patients with Alzheimer's disease (AD) experience concomitant psychiatric and behavioral complications, such as hallucinations, delusions, and aggression. Atypical antipsychotics (AAs) are used to treat psychosis and aggressive behaviors in these patients; however, data regarding their early effects on cognition are conflicting. Based on a literature search, the cognitive effects of long-term treatment with AAs in outpatients with AD have not been studied. OBJECTIVE: The aim of this study was to describe and compare the rate of cognitive decline with longterm AA use in adult patients with AD receiving concomitant treatment with cholinesterase inhibitors. METHODS: This study was conducted at the Department of Neurology, The Ohio State University, Columbus, Ohio. Data were collected from the charts of adult outpatients who (1) received care at Memory Disorders Clinic, Columbus, Ohio, between April 2003 and June 2005; (2) were aged > or =55 years with a diagnosis of mild to severe definite or probable AD; (3) received an AA for > or =6 months or did not receive any AA; and (4) received a cholinesterase inhibitor during the entire evaluation period. Cognitive function, as measured using the Mini-Mental State Examination (MMSE), was compared between those who received AA treatment and those who did not. The end point was the rate of decline in cognitive function, defined as annualized change in mean MMSE score from baseline to the end of follow-up. RESULTS: Ninety-two outpatients were included in the final analysis (67 women, 25 men; mean age, 72.4 years). Thirty-four patients received treatment with an AA for 6 > or =months (mean duration of treatment, 421 days) and 58 did not receive any AA treatment. Quetiapine (mean dose, 67 mg/d) was prescribed to 28 (82 %) of the patients receiving an AA. The AAs were prescribed for psychosis (15 [44%] patients), psychosis/agitation (11 [32%]), and agitation/aggression (8 [24%]). The baseline mean MMSE scores in patients receiving and not receiving an AA were 14.65 and 17.88, respectively (P = 0.021), with mean (SD) annual rates of cognitive decline of 3.03 (1.84) and 2.24 (1.27), respectively (P = NS). CONCLUSION: The results from this retrospective study of data from a small, selected group of outpatients with AD did not find a significant difference in the rate of cognitive decline between those who received an AA for > or =6 months and those who did not.

Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus.

Despite substantial progress in the development of antiretroviral regimens that durably suppress Human Immunodeficiency Virus (HIV) infection, new agents that maintain high efficacy while further optimizing the safety of lifelong, chronic therapy are needed. Tenofovir alafenamide (TAF; formerly known as GS-7340) is a novel prodrug of the antiviral acyclic nucleoside phosphonate tenofovir (TFV) with improved properties relative to tenofovir disoproxil fumarate (TDF). Although potent and generally well tolerated, TDF therapy has been associated with changes in markers of renal function, decreases in bone mineral density and a rare occurrence of serious renal adverse events, including Fanconi's Syndrome. The renal and bone toxicity observed with TDF is associated with high circulating plasma levels of TFV. TAF was discovered to be a more efficient prodrug able to further refine HIV therapy and better address life-long therapy in an older and increasingly comorbid HIV infected population. By enhancing stability in biological matrices while being rapidly activated in cells, TAF produces higher levels of intracellular TFV diphosphate, the pharmacologically active metabolite, in HIV-target cells at substantially reduced oral doses of TFV equivalents. All TFV released in the body is eventually eliminated renally; therefore, lowering the TFV equivalents administered reduces off-target kidney exposure. Effective therapy is thus achieved at approximately 90% lower systemic exposure to TFV, translating to statistically and clinically significant improvement in safety parameters associated with bone mineral density and markers of renal function.

Development of a Squamous Cell Carcinoma of the Hand and Wrist After Cardiac Transplantation.

Described are the findings in a 57-year-old man who developed a large carcinoma 2 years after heart transplantation. Mental anxiety or depression may have contributed to a delay in seeking medical care. The result was amputation of the right arm below the elbow.

Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors.

Clinical studies with tenofovir disoproxil fumarate, an oral prodrug of the nucleotide analog tenofovir, recently approved for the treatment of HIV, have demonstrated antiviral activity and good tolerability in HIV-infected patients. In order to better understand the cytotoxicity profile of tenofovir relative to the other nucleoside reverse transcriptase inhibitors (NRTIs), the in vitro effects of these agents were evaluated in various human cell types. Tenofovir inhibited the proliferation of liver-derived HepG2 cells and normal skeletal muscle cells with CC(50) values of 398 and 870 microM, respectively. In comparison, ZDV, ddC, ddI, d4T, and abacavir all showed lower CC(50) values in these two cell types. Evaluation of hematopoietic toxicity revealed that tenofovir was less cytotoxic towards erythroid progenitor cells (CC(50)>200 microM) than ZDV, d4T, and ddC (CC(50)=0.06-5 microM). Despite some degree of donor-to-donor variability, the inhibitory activity of the tested NRTIs against myeloid cell lineage, in the order of decreasing severity, was consistently ddC>ZDV>d4T>tenofovir>3TC. Finally, tenofovir showed substantially weaker effects on proliferation and viability of renal proximal tubule epithelial cells than cidofovir, a related nucleotide analog with the potential to induce renal tubular dysfunction. In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease.

Pulmonary tumor embolism syndrome from occult colonic adenocarcinoma.

Pulmonary tumor embolism syndrome is a rare phenomenon that can occur in patients who have an occult neoplasm that metastasizes. We describe a case of an elderly woman with an undiagnosed colon cancer who suffered from respiratory distress and compromised pulmonary blood flow from micrometastasis in the pulmonary arteries.

Isolated atrial amyloidosis and the importance of molecular classification.

Amyloid is identified microscopically as an amorphous extracellular hyaline material that exhibits "apple-green" birefringence with Congo red stains. Amyloid is not a chemically distinct entity, and currently available molecular methods are capable of identifying over 20 amyloidogenic precursor proteins. Some of the more common diseases associated with amyloidosis include plasma cell dyscrasias, chronic inflammatory disorders, hereditary-familial mutations involving transthyretin, Alzheimer's disease, and so-called "senile" or age-related amyloidosis. The amyloid deposits in these various diseases may be isolated to a single organ such as the heart or brain, or the amyloidosis may be systemic. The senile types of cardiac amyloidosis can result from overproduction of atrial natriuretic factor or from accumulation of otherwise normal or wild-type transthyretin. We present the case of an 83-year-old hospitalized woman with known atrial fibrillation and previous pacemaker implantation who had cardiac arrest unresponsive to attempted resuscitation. Autopsy disclosed prominent amyloidosis involving the left atrium, and subsequent molecular studies identified the amyloidogenic material as alpha atrial natriuretic factor. Since the clinical management and genetic implications of the various diseases associated with amyloidosis are markedly different, we stress the importance of molecular classification whenever possible.

Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: a brief history of stavudine (D4T) and its comparison with other dideoxynucleosides.

The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogues for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A number of previously synthesized nucleoside analogues were comparatively evaluated, and stavudine (D4T) emerged as a promising candidate for development. Following clinical evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Cutaneous clear-cell granular cell tumors: the histologic description of an unusual variant.

BACKGROUND: Granular cell tumors (GCTs) are neoplasms showing nerve sheath differentiation that can arise in the skin but, to our knowledge, have not been associated with significant clear-cell morphology. METHODS: Two patients developed four separate GCTs with distinctive, diffuse clear-cell change, which completely camouflaged the primary differentiation. The morphology, histochemistry and immunohistochemistry of the lesions are described and are compared with the presence and extent of clear-cell change in 14 other cases of GCTs. RESULTS: The index cases were relatively broad proliferations with uniform diffuse clear-cell change and only minimal overlying epidermal hyperplasia. Prominent lymphoid nodules were present at the periphery. These clear-cell granular tumors were positive for S-100 protein, p75, CD68, NKI/C3 and neuron-specific enolase and were negative for epithelial mucin, periodic acid-Schiff, carcinoembryonic antigen, HMB-45, Melan-A, smooth muscle actin, Leu7, synaptophysin, CD34, factor XIIIa, epithelial membrane antigen and cytokeratin. Three of the fourteen comparison cases were found to have no clear-cell change, eight showed focal clear-cell change and three showed moderate clear-cell change. CONCLUSIONS: The distinctive morphology and the immunohistochemical results are discussed in the context of the differential diagnosis of clear-cell cutaneous tumors.

Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors.

Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 microM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 microM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 microM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 microM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 microM) is not associated with mitochondrial toxicity.

Cutaneous leiomyoma with cytologic atypia, akin to uterine symplastic leiomyoma.

BACKGROUND: Smooth muscle tumors of the skin with cytologic pleomorphism and mitotic activity have traditionally been characterized as leiomyosarcomas, despite having a benign clinical course. In the uterus, there is a smooth muscle tumor known as symplastic leiomyoma, which typically has cytologic pleomorphism without significant mitotic activity. OBJECTIVE: The objective was to illustrate by case report the unusual histologic variant of the cutaneous pilar leiomyoma analogous to the symplastic leiomyoma of the uterus. METHODS: A 54-year-old woman presented with a clinical picture of cutaneous leiomyoma but had histologic features of nuclear hyperchromasia and pleomorphism, but rare mitoses. RESULTS: Management of this patient included excision of the involved area. CONCLUSION: Symplastic leiomyoma is an atypical uterine leiomyoma with cytologic atypia. We present the case of a patient with cutaneous leiomyomas that histologically demonstrated similar features to a uterine symplastic leiomyoma. We believe that this represents a distinct histologic variant of the cutaneous pilar leiomyoma analogous to the symplastic leiomyoma of the uterus.