Rare Case Report of Pilomatrical Carcinosarcoma in a Pediatric Patient.

We present a case report of the exceptionally rare pilomatrical carcinosarcoma in an even rarer pediatric age group, a 9-year-old female patient. The tumor showed biphasic pilomatrical carcinoma and malignant sarcomatous transformation. To date, the patient is healing well without signs of recurrence. Although limited clinical follow-up is available due to the recent diagnosis, this case may provide a rare look at the clinical outcome of this very rare tumor.

Rare Case of Lipomatous Mixed Tumor With Follicular Differentiation.

Cutaneous mixed tumors are adnexal neoplasms characterized by a mixture of epithelial, myoepithelial, and stromal components of varying proportions. The diagnosis may be of little challenge when chondroid or myxoid components are dominant. However, there are variants of the cutaneous mixed tumor where more uncommon features predominate, making the diagnosis more challenging. Here, we present a case of a rare variant of the cutaneous mixed tumor with extensive adipocytic and follicular differentiation. This is the second case of such a tumor reported to literature to our knowledge.

Genomic Adequacy from Solid Tumor Core Needle Biopsies of ex Vivo Tissue and in Vivo Lung Masses: Prospective Study.

Purpose To identify the variables and factors that affect the quantity and quality of nucleic acid yields from imaging-guided core needle biopsy. Materials and Methods This study was approved by the institutional review board and compliant with HIPAA. The authors prospectively obtained 232 biopsy specimens from 74 patients (177 ex vivo biopsy samples from surgically resected masses were obtained from 49 patients and 55 in vivo lung biopsy samples from computed tomographic [CT]-guided lung biopsies were obtained from 25 patients) and quantitatively measured DNA and RNA yields with respect to needle gauge, number of needle passes, and percentage of the needle core. RNA quality was also assessed. Significance of correlations among variables was assessed with analysis of variance followed by linear regression. Conditional probabilities were calculated for projected sample yields. Results The total nucleic acid yield increased with an increase in the number of needle passes or a decrease in needle gauge (two-way analysis of variance, P < .0001 for both). However, contrary to calculated differences in volume yields, the effect of needle gauge was markedly greater than the number of passes. For example, the use of an 18-gauge versus a 20-gauge biopsy needle resulted in a 4.8-5.7 times greater yield, whereas a double versus a single pass resulted in a 2.4-2.8 times greater yield for 18- versus 20-gauge needles, respectively. Ninety-eight of 184 samples (53%) had an RNA integrity number of at least 7 (out of a possible score of 10). Conclusion With regard to optimizing nucleic acid yields in CT-guided lung core needle biopsies used for genomic analysis, there should be a preference for using lower gauge needles over higher gauge needles with more passes. ©RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on October 21, 2016.

Keratoacanthoma and squamous cell carcinoma are distinct from a molecular perspective.

Keratoacanthoma is a controversial entity. Some consider keratoacanthoma as a variant of squamous cell carcinoma, whereas others see it as a distinct self-resolving squamoproliferative lesion. Our objective is to examine the relationship of keratoacanthoma with squamous cell carcinoma and normal skin by using DNA microarrays. DNA microarray studies were performed on formalin-fixed and paraffin-embedded blocks from ten cases of actinic keratoacanthoma utilizing the U133plus2.0 array. These results were compared with our previously developed microarray database of ten squamous cell carcinoma and ten normal skin samples. Keratoacanthoma demonstrated 1449 differentially expressed genes in comparison with squamous cell carcinoma (>5-fold change: P<0.01) with 908 genes upregulated and 541 genes downregulated. Keratoacanthoma showed 2435 differentially expressed genes in comparison with normal skin (>5-fold change: P<0.01) with 1085 genes upregulated and 1350 genes downregulated. The most upregulated genes, comparing keratoacanthoma with normal skin included MALAT1, S100A8, CDR1, TPM4, and CALM1. The most downregulated genes included SCGB2A2, DCD, THRSP, ADIPOQ, adiponectin, and ADH1B. The molecular biological pathway analysis comparing keratoacanthoma with normal skin showed that cellular development, cellular growth and proliferation, cell death/apoptosis, and cell cycle pathways are prominently involved in the pathogenesis of keratoacanthoma. The most enriched canonical pathways were clathrin-mediated endocytosis signaling, molecular mechanisms of cancer and integrin signaling. The distinctive gene expression profile of keratoacanthoma reveals that it is molecularly distinct from squamous cell carcinoma. The molecular pathways and genes differentially expressed in comparing keratoacanthoma with normal skin suggest that keratoacanthoma is a neoplasm that can regress due to upregulation of the cell death/apoptosis pathway.

A Rare Case of a Pilar Cyst With Ductal Differentiation.

Pilar cysts are common squamous-lined cysts that typically occur on the scalp. They are believed to arise from the isthmus of anagen hairs or from the sac surrounding catagen and telogen hairs. The authors describe a rare case of a pilar cyst with prominent ductal differentiation, presumably of eccrine derivation. Sweat duct differentiation has been described in a myriad of cutaneous neoplasms and rarely within epidermoid cysts. The authors could only find one other case in the literature describing a pilar cyst with sebaceous and apocrine differentiation. The clinicopathologic findings are described here.

Malignant melanoma with neural differentiation: an exceptional case report and brief review of the pertinent literature.

: The term neurotropic melanoma has been used to refer to malignant melanoma with associated infiltration of nerve or "neural differentiation"--that is, melanoma cells exhibiting cytological characteristics of nerve cells. Historically, neurotropic melanoma has generally been discussed within the context of desmoplastic melanoma. We report an exceptional case of melanoma notable for a very well-differentiated neural component that was contiguous with obvious overlying melanoma. After careful consideration of all pertinent histological features, the overall diagnostic impression was that of melanoma with associated "malignant neurotization." We have not encountered a previously reported case with such a well-differentiated neural component. The following article details our exceptional case of melanoma with "malignant neurotization" and presents a discussion of the differential diagnosis and brief review of the pertinent literature.

Defining the origins of Ras/p53-mediated squamous cell carcinoma.

The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli.

Differentiating cutaneous squamous cell carcinoma and pseudoepitheliomatous hyperplasia by multiplex qRT-PCR.

Squamous cell carcinoma is the second most common cutaneous malignancy. The diagnosis can occasionally be difficult as there are many lesions that are mimics, clinically and on pathologic examination. One of the most challenging lesions to differentiate from squamous cell carcinoma is pseudoepitheliomatous hyperplasia, a reactive proliferation of the epidermis that can be encountered secondary to a variety of inflammatory and neoplastic conditions. Utilizing the data set from our previously performed DNA microarray studies on formalin-fixed and paraffin-embedded tissue, we found that the genes C15orf48 and KRT9 had a distinct and robust gene expression pattern in distinguishing squamous cell carcinoma from pseudoepitheliomatous hyperplasia. C15orf48 had higher expression than KRT9 in squamous cell carcinoma, but lower expression than KRT9 in pseudoepitheliomatous hyperplasia. We developed and blindly validated a multiplex TaqMan PCR assay that utilizes these two highly discriminatory genes, which can be performed on material extracted from formalin-fixed and paraffin-embedded tissue. The TaqMan assay was able to differentiate squamous cell carcinoma from pseudoepitheliomatous hyperplasia in 54 of 58 cases (93%). Squamous cell carcinoma was accurately identified in 27 of 28 cases (96%); pseudoepitheliomatous hyperplasia in 27 of 30 cases (90%). This multiplex TaqMan PCR assay may be used as a helpful ancillary molecular diagnostic test to accurately distinguish squamous cell carcinoma from pseudoepitheliomatous hyperplasia in challenging cases.

SOX10 expression distinguishes desmoplastic melanoma from its histologic mimics.

Desmoplastic melanoma (DM) presents diagnostic challenges due to histologic mimics and limited immunohistochemical staining. Although S100 usually stains DM, other melanoma markers (HMB-45 and Melan-A) are often negative. Dermal/subcutaneous mimics of DM [spindle cell/poorly differentiated squamous cell carcinoma, atypical fibroxanthoma (AFX), and sarcoma] show negative or unreliable immunohistochemical staining. Recently, SOX10 expression has been shown to be a sensitive and specific marker of DM. However, there are no published studies comparing the sensitivity and specificity of SOX10 for DM compared with its most common histologic mimics of the dermis/subcutis. We examined 76 cases, including DM (n = 15), spindle cell/poorly differentiated carcinoma (n = 18), AFX (n = 13), sarcoma with spindled morphology (n = 20), and malignant peripheral nerve sheath tumor (MPNST) (n = 10). Most (75%, 15/20) of sarcomas were centered in the dermis/subcutis and included sarcoma not otherwise specified, DFSP with sarcomatous transformation and myxofibrosarcoma. SOX10 was diffusely positive in 100% (15/15) of DMs and showed focal staining in 30% (3/10) of MPNSTs. All other tumors were negative for SOX10 [0% (0/18) of carcinomas, 0% (0/13) of AFXs, 0% (0/20) of sarcomas]. In conclusion, SOX10 is a highly useful marker to confirm the diagnosis of DM. In our study, SOX10 showed 100% sensitivity for DM and SOX10 was negative in all histologic mimics of the dermis/subcutis, including spindle cell carcinoma, AFX and sarcomas. Similar to S-100 protein, some MPNSTs show scattered positivity but did not show diffuse positivity seen in DM.

Reticulin and NM23 staining in the interpretation of lymph nodal nevus rests.

Melanocytic nevus rests in lymph nodes are a known diagnostic challenge, especially in patients with a history of melanoma. Reticulin and NM23 have been studied in this context. The pattern of reticulin staining in melanomas surrounds groups/nests of melanocytes but individual cells in benign nevi. NM23, a metastasis-suppressor gene, has an association with metastatic potential in melanomas and some carcinomas. Twenty-eight cases (14 cases of metastatic melanoma to lymph nodes and 14 cases of lymph node nevus rests, all confirmed with Melan-A staining) were stained with reticulin and NM23. The pattern of reticulin staining was reported as surrounding groups if staining was noted in approximately 5-10 melanocytes in greater than 50% of the lesion but was otherwise reported as surrounding individual melanocytes. Cytoplasmic staining was considered to represent reactivity for NM23. Reticulin staining around groups of melanocytes was identified in all 14 cases of metastatic melanoma. Regarding nodal nevus rest cases, 12 of 14 cases (86%) demonstrated staining around individual melanocytes, whereas in 2 cases, reticulin surrounded melanocytic groups. NM23 staining was equivocal in all cases. Reticulin staining reliably invests groups of melanocytes in cases of metastatic melanoma, whereas in nodal nevus rests, it predominantly surrounds individual melanocytes. NM23 demonstrated no discriminatory value in this analysis. In cases in which a collection of melanocytes is present within a lymph node, reticulin deposition around individual melanocytes supports a diagnosis of lymph nodal nevus rest.

Differential gene expression profiling of primary cutaneous melanoma and sentinel lymph node metastases.

Limited understanding of molecular mechanisms of metastasis in melanoma contributes to the absence of effective treatments. Increased knowledge of alterations in genes that underpin critical molecular events that lead to metastasis is essential. We have investigated the gene expression profiles of primary melanomas and melanoma metastases in sentinel lymph nodes. A total of 19 samples (10 primary melanomas and 9 sentinel lymph node metastases) were evaluated. Melanoma cells were dissected from tissue blocks. Total mRNA was isolated, amplified, and labeled using an Ambion Recover All Total Nucleic Acid Isolation kit, Nu-GEN WT-Ovation formalin-fixed, paraffin-embedded RNA Amplification System, and FL-Ovation cDNA Biotin Module V2, respectively. Samples were hybridized to the Affymetrix Gene Chip Human U133 Plus 2.0 Array. Data were analyzed using Partek Genomics Suite Version 6.4. Genes selected showed ≥2-fold difference in expression and P<5.00E-2. Validation studies used standard immunohistochemical assays. Hierarchical clustering disclosed two distinct groups: 10 primary melanomas and 9 sentinel lymph node metastases. Gene expression analysis identified 576 genes that showed significant differential expression. Most differences reflected decreased gene expression in metastases relative to primaries. Reduced gene expression in primaries was less frequent and less dramatic. Genes significantly increased or decreased in sentinel lymph node metastases were active in cell adhesion/structural integrity, tumor suppression, cell cycle regulation, and apoptosis. Validation studies indicate that MAGEC1 (melanoma antigen family C1) and FCRL1 (Fc receptor-like 1) are involved in melanoma progression. There are striking differential gene expression patterns between primary and nodally metastatic melanomas. Similar findings were seen with autologous paired primary melanomas and sentinel lymph node metastases, supporting involvement of these gene alterations in evolution of metastases. With further study, it may be possible to determine the exact sequence of molecular events that underlie melanoma metastases.

Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV.

MOTIVATION: The ability to detect copy-number variation (CNV) and loss of heterozygosity (LOH) from exome sequencing data extends the utility of this powerful approach that has mainly been used for point or small insertion/deletion detection. RESULTS: We present ExomeCNV, a statistical method to detect CNV and LOH using depth-of-coverage and B-allele frequencies, from mapped short sequence reads, and we assess both the method's power and the effects of confounding variables. We apply our method to a cancer exome resequencing dataset. As expected, accuracy and resolution are dependent on depth-of-coverage and capture probe design. AVAILABILITY: CRAN package 'ExomeCNV'. CONTACT: fsathira@fas.harvard.edu; snelson@ucla.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cutaneous ciliated cyst on the finger: a cutaneous mullerian cyst.

As previously recognized by various authors, "cutaneous ciliated cyst" is a confusing term. Typically, the term refers to rare cystic lesions, commonly found on the lower limbs of women in their reproductive years. To date, 40 cases diagnosed as "cutaneous ciliated cyst" have been reported in the literature. Histologically, the cysts are composed of a simple layer of ciliated columnar cells along with nonciliated columnar cells, cuboidal cells, and round "peg-like" cells, resembling fallopian tube epithelium. This histology has been described in cysts found in males and females and in locations other than the lower limbs. Controversy has thus arisen over the etiology of these lesions, with some believing that the cysts arise from heterotopic Mullerian rests and others advocating for ciliated metaplasia of eccrine glands. We herein describe the first case of cutaneous ciliated cyst of Mullerian origin occurring on the dorsal thumb of a 16-year-old female. A review of literature shows that 2 groups of cysts are covered under the umbrella term "cutaneous ciliated cysts." We thus propose the abandonment of the confusing term "cutaneous ciliated cyst" and the adoption of "cutaneous Mullerian cysts" for estrogen receptor/progesterone receptor-positive lesions resembling simple fallopian tube epithelium and "Cutaneous ciliated eccrine cyst" for estrogen receptor/progesterone receptor-negative lesions usually occurring in males, which are immunohistochemically compatible with an eccrine origin.

Sentinel lymph node melanoma metastases: Assessment of tumor burden for clinical prediction of outcome in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

PURPOSE: As clinical management decisions in patients with Stage III melanoma have become more complex, precise pathologic characterization of sentinel lymph node (SLN) metastases has become critical to guide management. The extent of SLN involvement correlates with risk of adverse outcomes, but reported methods of disease quantification vary. We examined SLN metastases from patients participating in an international clinical trial and compared several methods of tumor burden quantification. METHODS: SLNs from 146 node-positive patients in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were centrally-reviewed and characterized by number of tumor-positive nodes, percent nodal area tumor replacement, maximum dimension of largest metastasis, tumor penetrative depth, number of tumor foci, metastasis microanatomic location, and extracapsular extension. These data were analyzed for correlation with non-SLN metastasis and melanoma-specific survival (MSS). RESULTS: The median number of tumor-involved SLNs was 1. The median maximum metastasis dimension was 1.11 mm. Median SLN area involvement was 1.5%. Tumor burden measures were highly correlated with each other. Factors associated with non-SLN metastasis by univariable analysis were primary tumor ulceration and extent of metastases. Tumor thickness, ulceration, non-SLN metastasis and multiple measures of SLN tumor burden were significantly related to MSS on univariable analysis. After multivariable adjustment, number of involved SLNs (p = 0.05) and percent nodal area tumor replacement (p = 0.02) were independent predictors of MSS. CONCLUSION: Central review of MSLT-I pathology indicates that primary tumor and SLN tumor characteristics predict non-SLN metastasis and MSS. Percent nodal involvement was more powerfully prognostic than the more commonly used maximum dimension of largest metastasis.

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin.

Actinic keratosis is widely believed to be a neoplastic lesion and a precursor to invasive squamous cell carcinoma. However, there has been some debate as to whether actinic keratosis is in fact actually squamous cell carcinoma and should be treated as such. As the clinical management and prognosis of patients is widely held to be different for each of these lesions, our goal was to identify unique gene signatures using DNA microarrays to discriminate among normal skin, actinic keratosis, and squamous cell carcinoma, and examine the molecular pathways of carcinogenesis involved in the progression from normal skin to squamous cell carcinoma. Formalin-fixed and paraffin-embedded blocks of skin: five normal skins (pooled), six actinic keratoses, and six squamous cell carcinomas were retrieved. The RNA was extracted and amplified. The labeled targets were hybridized to the Affymetrix human U133plus2.0 array and the acquisition and initial quantification of array images were performed using the GCOS (Affymetrix). The subsequent data analyses were performed using DNA-Chip Analyzer and Partek Genomic Suite 6.4. Significant differential gene expression (>2 fold change, P<0.05) was seen with 382 differentially expressed genes between squamous cell carcinoma and normal skin, 423 differentially expressed genes between actinic keratosis and normal skin, and 9 differentially expressed genes between actinic keratosis and squamous cell carcinoma. The differentially expressed genes offer the possibility of using DNA microarrays as a molecular diagnostic tool to distinguish between normal skin, actinic keratosis, and squamous cell carcinoma. In addition, the differentially expressed genes and their molecular pathways could be potentially used as prognostic markers or targets for future therapeutic innovations.

Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis.

Neurothekeomas and dermal nerve sheath myxomas have previously been considered related cutaneous neoplasms of peripheral nerve sheath origin based on light microscopic similarities. However, recent immunohistochemical and ultrastructural data indicate nerve sheath myxomas exhibit true nerve sheath differentiation, whereas no such compelling evidence exists for neurothekeomas. Although neurothekeomas lack a specific immunohistochemical profile, similar antigen expression and histopathologic patterns suggest neurothekeomas may be categorized as fibrohistiocytic tumors. To date, no known molecular studies have examined the histogenetic relationship of these tumors. We report the first microarray-based gene expression profile study of these entities on formalin-fixed paraffin-embedded tissues. Cases of dermal schwannomas, dermal nerve sheath myxomas, myxoid/mixed/cellular neurothekeomas, and cellular fibrous histiocytomas diagnosed in the past 3 years were identified in our database. Archival formalin-fixed paraffin-embedded tissue from 28 patients was selected for microarray analysis (seven schwannomas, five nerve sheath myxomas, nine myxoid/mixed/cellular neurothekeomas and seven cellular fibrous histiocytomas). Following tumor RNA isolation, amplification and labeling using commercially available kits, labeled targets were hybridized to the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array (Santa Clara, CA, USA). Acquisition of array images and data analyses was performed using appropriate software. Hierarchical clustering and principal component analysis demonstrated discrete groups, which correlated with histopathologically identified diagnoses. Dermal nerve sheath myxomas demonstrate very similar molecular genetic signatures to dermal schwannomas, whereas neurothekeomas of all subtypes more closely resemble cellular fibrous histiocytomas. We are the first to report distinct gene expression profiles for nerve sheath myxomas and neurothekeomas, which further substantiates the argument that these are separate entities. Our molecular data confirms that dermal nerve sheath myxomas are of peripheral nerve sheath origin, and suggests that neurothekeomas may actually be a variant of fibrous histiocytomas.

Clinically relevant information from sentinel lymph node biopsies of melanoma patients.

Careful laboratory evaluation of sentinel nodes (SNs) is critical to determine the presence of tumor. This requires evaluation of multiple full-face sections from the SN, using H&E staining and immunohistochemistry. In the future, molecular and genetic approaches may be adjunctive to microscopy. Number of tumor-positive SNs and the amount and location of tumor in SNs correlate with tumor spread to non-sentinel nodes, subsequent recurrences and melanoma death, permitting patient assignment to a risk category.

Melanocytic matricoma with melanocytic atypia: report of a unique case and review of the literature.

Melanocytic matricoma is a rare cutaneous neoplasm of presumed anagen hair follicle origin with approximately 10 reported cases in the literature. Melanocytic matricomas are clinically and histopathologically distinct cutaneous nodular proliferations of matrical and supramatrical cells admixed with dendritic melanocytes, which typically occur in the sun-exposed areas of elderly patients. We report a new case with additional histopathologic features not previously described. An 82-year-old white man presented with an exophytic papule of the ear clinically suspicious for basal cell carcinoma. Histopathologic examination demonstrated a polypoid neoplasm consisting of an admixture of matrical and shadow cells with numerous interspersed dendritic and epithelioid melanocytes arranged singly and in large expansile nests. An unusual feature in this case included prominent melanocytic proliferation with associated nuclear atypia and increased mitotic activity. Although atypical and malignant melanocytic colonization has been reported in basal cell carcinomas and squamoproliferative lesions, to our knowledge, it has not been previously described in melanocytic matricomas. The biologic significance of atypical melanocytic proliferations within melanocytic matricomas is uncertain and requires further study of additional cases and long-term follow-up.

Potentially useful markers for desmoplastic melanoma: an analysis of KBA.62, p-AKT, and ezrin.

Desmoplastic melanoma (DM) represents only a small portion of newly diagnosed melanoma cases but can be a significant diagnostic challenge for dermatopathologists. Immunohistochemical stains are often useful to confirm the diagnosis; however, DM is notorious for not expressing most of the melanocytic markers other than S100. Recent studies have suggested several new markers, which may be promising in the diagnosis of DM. KBA.62 is a relatively new antimelanoma monoclonal antibody, which has not been well characterized in DM. Ezrin and p-Akt are additional markers, which have been shown to be involved in cell survival and proliferation. We collected 12 cases of DM and 18 cases of other lesions that could be included in the differential diagnosis. The H&E sections were reviewed, and immunohistochemical stains for KBA.62, p-AKT, and Ezrin were performed. Seventy-five percent of the DM cases (9 of 12) demonstrated positive staining (>5% of tumor cells staining) with KBA.62, with an average of 39% of cells staining. One hundred percent of the DM cases (12 of 12) demonstrated positive staining with Ezrin, with an average of 49% of tumor cells staining. Seventy-five percent of the DM cases (9 of 12) demonstrated positive staining with p-Akt, with an average of 49% of cells staining. KBA.62 and Ezrin demonstrated statistically significant increased staining of DM cases compared with the other lesions (P = 0.05 and P = 0.007, respectively), although it was not useful in distinguishing DM versus malignant peripheral nerve sheath tumor, whereas p-Akt showed no significant differences in staining between DM and the other cases. These findings suggest that KBA.62 may be a useful marker in confirming the diagnosis of DM.