Cutaneous ciliated cyst of the scalp: a case report of a cutaneous ciliated eccrine cyst and a brief review of the literature.

Cutaneous ciliated cysts (CCC) are rare benign cysts known to occur in the lower extremities of females of reproductive age. Currently, there are 2 theories that attempt to explain the histogenesis of this rare entity. The theory of Mullerian heterotopia provides a plausible histogenetic explanation for the vast majority of CCC. A proposed alternative theory is the ciliated metaplasia of eccrine glands. We believe that previously reported cases of CCC include 2 distinct entities. We report, herein, the first case reported in the literature of a cutaneous ciliated eccrine cyst occurring on the scalp.

Cutaneous erosions: a herald for impending pancytopenia in methotrexate toxicity.

Psoriatic plaque erosion is a rare toxic side effect of low-dose methotrexate (LDMTX) that has been reported during the treatment of psoriasis and described as a herald for impending pancytopenia. Fatalities from this have rarely been reported. Even rarer is methotrexate (MTX)-induced erosions of clinically normal skin in patients without a history of psoriasis. We report 3 rare presentations of MTX-induced cutaneous erosions, 2 fatalities occurring with MTX-induced psoriatic plaque erosions, and the sixth reported case of MTX-induced erosions with no prior history of psoriasis. Each were elderly patients on proton pump inhibitors with a history of chronic non-steroidal anti-inflammatory drug (NSAID) use. They all presented with acute onset of erosions after a recent change in their MTX dose. Pancytopenia followed in each case. Physicians' awareness of the sequelae in MTX-induced cutaneous erosions is imperative so MTX can be discontinued and treatment instituted to prevent fatal bone marrow suppression.

High-Grade Atypical Teratoid/Rhabdoid Tumor in the Pituitary Region.

Atypical teratoid/rhabdoid tumors (AT/RTs) are embryological tumors of the central nervous system (CNS). They are typically found in children, with rare presentations in adults. We describe the presentation of an AT/RT in the pituitary region of a 37-year-old female. The patient presented with a two-week history of intractable cephalgia with sudden onset of monocular diplopia and left-sided cranial nerve VI palsy. The patient underwent transsphenoidal resection of their mass, which revealed the diagnosis. She then underwent systemic therapy with chemotherapy as well as radiation. She ultimately died 14 months after treatment completion due to unrelated events. The case highlights the rarity of AT/RT in adults, emphasizing the challenge of establishing standardized treatment protocols due to its rarity in adult presentations.

Multifocal Extramedullary Plasmacytoma of the Thyroid With Cervical and Paratracheal Lymph Node Involvement and Progression to Multiple Myeloma.

Extramedullary plasmacytomas without evidence of systemic illness make up less than 5% of all plasma cell neoplasms. The incidence of extramedullary plasmacytoma of the thyroid region is exceedingly rare. This report discusses the case of a 72-year-old male with extramedullary plasmacytoma of the thyroid. The patient underwent a total thyroidectomy for an enlarging right-sided thyroid nodule, and intraoperatively, the plasmacytoma was found to have an extracapsular component with adherence to the regional soft tissue as well as involvement of the right laryngeal nerve and regional lymph nodes. Despite a comprehensive negative workup for multiple myeloma initially, including a bone marrow biopsy and hematologic workup, the disease progressed to multiple myeloma following definitive radiation therapy, as evidenced by the development of hypermetabolic lytic lesions and further pathological examination. The patient's treatment course included systemic chemotherapy and an autologous stem cell transplant, resulting in a favorable treatment response. The progression to multiple myeloma despite established guidelines highlights the need for close observation and the potential for innovative therapeutic strategies to manage this rare entity.

The spectrum of histopathologic findings in cutaneous eruptions associated with influenza A (H1N1) infection.

Influenza A (H1N1), like many other viral infections, has been associated with cutaneous eruptions. Differential diagnoses in a viral exanthem generally include spongiotic dermatitis, urticaria and drug reaction. The aim of this series was to retrospectively review three cases (five biopsies) involving patients with a clinical history of H1N1 and an accompanying rash, and to evaluate whether unique histopathologic and immunohistochemical features exist among these patients' cutaneous eruptions. Findings among all cases included a sparse superficial perivascular infiltrate, and interestingly, scattered interstitial and prominent intravascular neutrophils. Two cases demonstrated mild spongiosis and mild interface change. Immunohistochemistry in all cases revealed a CD4-predominant lymphocytic infiltrate of the dermis with a sparse intraepidermal population of admixed CD4 and CD8 positive lymphocytes. Many changes found in the cutaneous eruption associated with H1N1 are similar to those of other viral eruptions, including a mild perivascular lymphocytic infiltrate, mild spongiosis and mild interface change; however, sparse dermal and intravascular neutrophils and intraepidermal lymphocytes appear to be the features unique to these cases of H1N1-associated cutaneous eruptions. Such a distinction may prove diagnostically important in the clinical setting and useful in the surveillance of this historically pandemic virus.

A case of cutaneous Scedosporium infection in an immunocompromised patient.

Scedosporium apiospermum, the asexual stage of Pseudoallescheria boydii, is a fungus ubiquitous in soil as well as organically polluted areas, where nitrogen-containing compounds are abundant. It is an emerging opportunistic pathogen that can range from cutaneous to disseminated infection and can be fatal within months of diagnosis. Here we present a case of disseminated S. apiospermum infection with cutaneous manifestations in a 59-year-old woman with myelodysplastic syndrome, in remission from chronic lymphocytic leukemia, presented with pneumonia and deteriorating mental status. An X-ray computed tomography scan showed three non-contrast-enhancing hypodensities affecting the brain. Many erythematous, indurated skin lesions, measuring 3-5 mm in diameter, were noted on her chest, shoulders and arms. Biopsies were submitted for culture and histology. Histopathologic examination revealed superficial and deep perivascular and periadnexal inflammatory infiltrates of lymphocytes and neutrophils. Scattered collections of fungal organisms were noted near the eccrine glands. The periodic acid Schiff with diastase stain showed the presence of variable sized spores and hyphae with some acute angle branching. Both tissue and blood cultures were positive for a single Scedosporium species. Histologically, eccrine or peri-eccrine involvement by fungi may be an important finding for Scedosporium infection of the skin.

Amelanotic melanoma: a detailed morphologic analysis with clinicopathologic correlation of 75 cases.

Amelanotic melanoma can have a varied appearance both clinically and microscopically. Here, we present our experiences with 75 cases of amelanotic melanoma defined clinically as a non-pigmented lesion and histopathologically as a tumor lacking significant melanization. We evaluated microscopic features such as morphology, mitotic count, nuclear atypia and presence of solar elastosis. Our amelanotic melanomas exhibited the following morphology: epitheloid (72%), spindled (18.7%) or desmoplastic (5.3%). In addition, we obtained patient information and clinical presentations on most of the cases (74/75; 98.7%) and follow-up data on 40% (30/75) of the cases. The majority of amelanotic melanomas in men were found on the trunk (13/45; 29%), head and neck (12/45; 26.7%), and lower limb (13/45; 29%) and in women were found on the lower limb (12/30; 40%), upper limb (10/30; 33.3%) and head and neck (6/30; 20%). In addition, we found that an increase in mitotic index correlated with worse survival (p < 0.026), whereas there were no differences in survival for other pathological features, such as nuclear atypia or solar elastosis. Furthermore, in cases with available tissue, all amelanotic melanoma expressed microphthalmia-associated transcription factor and tyrosinase, suggesting that the tumor cells retained melanocytic lineage and an enzyme in melanin formation, respectively. As the occurrence of amelanotic melanoma and the expression melanoma markers were similar to pigmented melanoma, we favor that amelanotic melanoma represents a subtype of melanoma rather than poorly differentiated or de-differentiated melanoma.

Misregulation of Rad50 expression in melanoma cells.

DNA double-strand breaks are increased in human melanoma tissue as detected by histone H2AX phosphorylation.(1-3) We investigated two of the downstream effectors of DNA double-strand breaks, Rad50 and 53BP1 (tumor suppressor p53 binding protein 1), to determine if they are altered in human primary melanoma cells. Melanoma cases showed high Rad50 staining (81.8%; 9/11) significantly more frequently than conventional or atypical melanocytic nevi (0%; 0/18). In contrast, the staining pattern for 53BP1 appears similar between melanoma and nevi. This is the first study that shows activation and misregulation of the DNA repair pathway in human melanoma cells. The staining features of Rad50, a component of an essential DNA double-strand break repair complex, are clearly increased in melanoma cells with regards to both staining intensity and the number of positive melanoma cells. Interestingly, among the melanoma cases with increased Rad50 staining, most demonstrated cytoplasmic rather than nuclear staining (88.9%, 8/9). Further studies are needed to determine the cause of this mislocalization and its affects, if any, on DNA double-strand break repair in melanoma.

Collapsing angiokeloidal dermatofibroma.

A heterogeneous group of benign fibrohistiocytic lesions has been assembled under the umbrella term, dermatofibroma. These lesions share a morphology of bland spindled cells encompassed by and intercalating through thick dermal collagen; unique variants have been described based on secondary histologic features, some of which include aneurysmal, myxoid, lipidized, signet ring, angiomatous, and keloidal. Here, we present a distinct dermatofibroma variant henceforth known as collapsing angiokeloidal dermatofibroma identified in 2 patients with slowly growing nodules of the buttock and the arm. Microscopically, the lesions have a characteristic dermatofibroma appearance but are accompanied by unusual diffuse small caliber vessels whose walls are collapsed by a thick, eosinophilic, keloid-like substance. The eosinophilic material resembles the adjacent dermal collagen; however, it does not stain for type-4 collagen or type-1 procollagen, amyloid, or glycogen. Although the exact composition of the keloidal material remains ambiguous, the architectural novelty of collapsing angiokeloidal dermatofibroma serves to further expand the morphologic spectrum of benign fibrous histiocytomas, although highlighting the difficulty in distinguishing between it and similar lesions.

Intraoperative sentinel lymph node analysis in melanoma.

BACKGROUND: The objective of this retrospective cohort study was to evaluate the sensitivity and specificity of touch preparation cytology (TPC) and frozen section (FS) histology in the intraoperative staging of melanoma. METHODS: The cohort was identified from all patients with clinically node negative melanoma undergoing a SLN biopsy using Technetium and/or blue dye mapping from 1/1998 to 10/2008. TPC and FS analysis was performed utilizing Diff-quick and compared to permanent section interpretation with H&E. RESULTS: Of 271 patients undergoing SLN biopsy, 163 underwent intraoperative analysis of the sentinel node (125 underwent TPC alone, 15 underwent FS alone, 23 underwent both TPC and FS), and 108 underwent no intraoperative analysis. Thirty-three patients undergoing intraoperative analysis of the SLN were found to have positive nodes (20%) on permanent histology. There were no false positives identified (specificity = 100%). The overall sensitivity for all methods of intraoperative analysis was 61% (20/33). On a per patient basis, the sensitivity was 47% (9/19) for TPC alone, 75% (3/4) for FS alone, and 80% (8/10) for both TPC and FS. CONCLUSIONS: There were no false positives identified suggesting TPC and FS can be used safely to identify the majority of SLN that harbor metastases from melanoma.

Phosphorylated H2AX in noninvasive low grade urothelial carcinoma of the bladder: correlation with tumor recurrence.

PURPOSE: Histone modifications have been linked to DNA replication, transcription and repair. The phosphorylation of histone H2AX at serine 139 (gamma-H2AX) is associated with DNA breaks. gamma-H2AX has been shown to be expressed in bladder urothelial carcinoma. To our knowledge studies of the relationship of gamma-H2AX expression and the clinical outcome of urothelial carcinoma are lacking. Hence, we evaluated the rate of H2AX phosphorylation in low grade bladder urothelial carcinoma and assessed its potential role for predicting recurrence and/or progression. MATERIALS AND METHODS: Immunohistochemical expression of gamma-H2AX using a polyclonal antibody was retrospectively assessed in 2 groups of patients from The Johns Hopkins Hospital with low grade bladder urothelial carcinoma. Group 1 consisted of transurethral resection biopsies from 18 patients from 2004 to 2006 that were retrieved from our surgical pathology files. Group 2 consisted of 42 archival transurethral biopsies obtained between 1971 and 1995 with longer followup that were used to construct a tissue microarray. RESULTS: On univariate analysis recurrence in the entire cohort was more likely to develop in gamma-H2AX negative than in gamma-H2AX positive cases (24 of 32 or 81% vs 13 of 28 or 46%). The difference in recurrence was statistically significant (p = 0.02). The same was true in group 2 (16 of 21 cases or 76% vs 9 of 21 or 43%, p = 0.02). Female gender and intravesical therapy were also associated with a higher recurrence rate in our cohort. A higher progression rate was noted in group 2 patients and in the entire cohort in association with negative gamma-H2AX staining. However, the difference in progression between gamma-H2AX negative and positive tumors was not statistically significant. On multivariate analysis only patient gender and prior intravesical treatment remained predictive of recurrence (p <0.03). CONCLUSIONS: Our data suggest that epigenetic alterations may have an important role in the mechanism of bladder tumor recurrence. Analysis in a larger cohort is needed to further assess our current preliminary findings of the role of gamma-H2AX expression for predicting outcome in low grade urothelial carcinoma cases.

Phosphorylation of histone H4 serine 1 during DNA damage requires casein kinase II in S. cerevisiae.

Distinct patterns of posttranslational histone modifications can regulate DNA-templated events such as mitosis, transcription, replication, apoptosis, and DNA damage, suggesting the presence of a "histone code" in these nuclear processes. Phosphorylation of histone H2A S129 at sites of DNA double-strand breaks (DSBs) has been implicated in damage repair in yeast. Here, we describe another phosphorylation event on serine 1 (S1) of histone H4; this event is also associated with MMS- or phleomycin-induced DSBs but not with UV-induced DNA damage. Chromatin-immunoprecipitation (ChIP) studies of an HO-endonuclease-inducible strain show that S1 phosphorylation is specifically enhanced 20- to 25-fold in nucleosomes proximal to the DSB. In addition, we show that casein kinase II (CK2) can phosphorylate H4 S1 in vitro and that null or temperature-sensitive CK2 yeast mutants are defective for induction of H4 S1 phosphorylation upon DNA damage in vivo. Furthermore, H4 S1 phosphorylation and CK2 play a role in DSB re-joining as indicated by a nonhomologous end-joining (NHEJ) plasmid assay. CK2 has been implicated in regulating a DNA-damage response; our data suggest that histone H4 S1 is one of its physiological substrates. These data suggest that this modification is a part of the DNA-repair histone code.

Colonic-type adenocarcinoma arising in a primary retroperitoneal mature cystic teratoma.

A 47-year-old woman who presented with abdominal pain was found to have a 20 cm cystic retroperitoneal mass. Pathology indicated a colonic-type adenocarcinoma arising in a primary retroperitoneal mature cystic teratoma. The adenocarcinoma was predominantly intracystic with focal superficial invasion into the cyst wall but not beyond the teratoma capsule. Immunohistochemistry showed that the adenocarcinoma cells were diffusely positive for cytokeratin 20 (CK20) and caudal-type homeobox transcription factor-2 (CDX2) but negative for CK7, confirming the colonic phenotype. In addition, the adenocarcinoma was seen adjacent to teratomatous colonic-type mucosa with adenomatous change (i.e. adenoma), suggesting that it was probably arising from a colonic-type adenoma within the teratoma. The carcinoma had a higher Ki-67 proliferation index and had a higher percentage of cells stained for p53 than the adjacent adenomatous lesion. To the authors' knowledge this is the first documented case in which a colonic-type adenocarcinoma was seen arising from a precursor lesion (i.e. a colonic-type adenoma in a primary retroperitoneal mature cystic teratoma) and is the second case of intestinal-type adenocarcinoma arising in a primary retroperitoneal mature cystic teratoma.

Chromatin immunoprecipitation assay for mammalian tissues.

In this postgenome era, understanding how a cell regulates access to information encoded in the deoxyribonucleic acid (DNA) is essential. In eukaryotic cells, DNA is bound to histone proteins to form chromatin fibers. Numerous studies have now shown that post-translational histone modifications play an important role in regulating the access of DNA-dependent proteins to the DNA template. Determining the status of histone modifications in a genomic region has proven to yield information on the chromatin structure and the regulation of a specific gene in vivo. Chromatin immunoprecipitation (ChIP) allows researchers to determine the status of both histone modifications and the nuclear effector proteins located at gene of interest. ChIP, if applied globally, can also reveal how chromatin structures are dynamically changed when cells respond to certain stimuli. In this chapter, we describe this powerful technique in detail.

Acne Treatment Based on Selective Photothermolysis of Sebaceous Follicles with Topically Delivered Light-Absorbing Gold Microparticles.

The pathophysiology of acne vulgaris depends on active sebaceous glands, implying that selective destruction of sebaceous glands could be an effective treatment. We hypothesized that light-absorbing microparticles could be delivered into sebaceous glands, enabling local injury by optical pulses. A suspension of topically applied gold-coated silica microparticles exhibiting plasmon resonance with strong absorption at 800 nm was delivered into human pre-auricular and swine sebaceous glands in vivo, using mechanical vibration. After exposure to 10-50 J cm(-2), 30 milliseconds, 800 nm diode laser pulses, microscopy revealed preferential thermal injury to sebaceous follicles and glands, consistent with predictions from a computational model. Inflammation was mild; gold particles were not retained in swine skin 1 month after treatment, and uptake in other organs was negligible. Two independent prospective randomized controlled clinical trials were performed for treatment of moderate-to-severe facial acne, using unblinded and blinded assessments of disease severity. Each trial showed clinically and statistically significant improvement of inflammatory acne following three treatments given 1-2 weeks apart. In Trial 2, inflammatory lesions were significantly reduced at 12 weeks (P=0.015) and 16 weeks (P=0.04) compared with sham treatments. Optical microparticles enable selective photothermolysis of sebaceous glands. This appears to be a well-tolerated, effective treatment for acne vulgaris.

Quantitative Proteomics Identifies Activation of Hallmark Pathways of Cancer in Patient Melanoma.

Molecular pathways regulating melanoma initiation and progression are potential targets of therapeutic development for this aggressive cancer. Identification and molecular analysis of these pathways in patients has been primarily restricted to targeted studies on individual proteins. Here, we report the most comprehensive analysis of formalin-fixed paraffin-embedded human melanoma tissues using quantitative proteomics. From 61 patient samples, we identified 171 proteins varying in abundance among benign nevi, primary melanoma, and metastatic melanoma. Seventy-three percent of these proteins were validated by immunohistochemistry staining of malignant melanoma tissues from the Human Protein Atlas database. Our results reveal that molecular pathways involved with tumor cell proliferation, motility, and apoptosis are mis-regulated in melanoma. These data provide the most comprehensive proteome resource on patient melanoma and reveal insight into the molecular mechanisms driving melanoma progression.

Dermatopathology updates on melanocytic lesions.

This article provides an update on histopathologic studies of different types of melanocytic lesions, such as site-specific nevi, "Spark's" nevi, nevi during pregnancy, and atypical dermal melanocytic proliferation, including pigmented epithelioid melanocytoma, proliferating nodules, and atypical Spitzoid tumor. Special-site nevi, such as those appearing on the breast and genital region, generally have more cytologic and architectural atypia. Melanocytic proliferations generally do not change during pregnancy, contrary to earlier observations. Atypical dermal melanocytic proliferations are difficult to diagnose and usually have a better outcome after adequate treatment, including wide local skin excision with or without sentinel lymph node resection.

Analysis of Histone Exchange during Chromatin Purification.

Central to the study of chromosome biology are techniques that permit the purification of small chromatin sections for analysis of associated DNA and proteins, including histones. Chromatin purification protocols vary greatly in the extent of chemical cross-linking used to prevent protein dissociation/re-association during isolation. Particularly for genome-wide analyses, chromatin purification requires a balanced level of fixation that captures native protein-protein and protein/DNA interactions, yet leaving chromatin sections soluble and accessible to affinity reagents. We have applied a relative quantification methodology called I-DIRT (isotopic differentiation of interactions as random or targeted) for optimizing levels of chemical cross-linking for affinity purification of cognate chromatin sections. We show that fine-tuning of chemical cross-linking is necessary for isolation of chromatin sections when minimal histone/protein exchange is required.

Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis.

Sporulation in Saccharomyces cerevisiae is a highly regulated process wherein a diploid cell gives rise to four haploid gametes. In this study we show that histone H4 Ser1 is phosphorylated (H4 S1ph) during sporulation, starting from mid-sporulation and persisting to germination, and is temporally distinct from earlier meiosis-linked H3 S10ph involved in chromosome condensation. A histone H4 S1A substitution mutant forms aberrant spores and has reduced sporulation efficiency. Deletion of sporulation-specific yeast Sps1, a member of the Ste20 family of kinases, nearly abolishes the sporulation-associated H4 S1ph modification. H4 S1ph may promote chromatin compaction, since deletion of SPS1 increases accessibility to antibody immunoprecipitation; furthermore, either deletion of Sps1 or an H4 S1A substitution results in increased DNA volume in nuclei within spores. We find H4 S1ph present during Drosophila melanogaster and mouse spermatogenesis, and similar to yeast, this modification extends late into sperm differentiation relative to H3 S10ph. Thus, H4 S1ph may be an evolutionarily ancient histone modification to mark the genome for gamete-associated packaging.