A standardized approach to classifying melanocytic neoplasms? Comments on the MPATH-Dx system.

The potential benefits and limitations of the MPATH-Dx classification system for melanocytic neoplasms are presented and discussed.

Proliferative nodule resembling angiomatoid Spitz tumor with degenerative atypia arising within a giant congenital nevus.

Proliferative nodules arising within congenital melanocytic nevi often present a diagnostic challenge given a close resemblance to melanoma. Several morphologic variants have been characterized. In difficult cases, ancillary molecular tests can be used to better exclude the possibility of malignant degeneration. Herein, we report a case of an unusual proliferative nodule with overlapping features of angiomatoid Spitz tumor and ancient melanocytic nevus, which demonstrated normal findings on both chromosomal microarray and a gene expression profiling assay.

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi.

BACKGROUND: Recently, a 23-gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. METHODS: A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. RESULTS: The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. CONCLUSIONS: These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617-628. © 2016 American Cancer Society.

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.

BACKGROUND: Disease-specific skin lesions are rare in patients with multiple myeloma (MM). OBJECTIVE: We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. METHODS: We identified 13 patients with cutaneous lesions of MM. RESULTS: Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. LIMITATIONS: The study group was relatively small. CONCLUSIONS: Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival.

Gamma-delta T-cell lymphoma arising in a long-standing cutaneous plaque.

The precise classification and characterization of primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) has been hindered by clinical and morphologic features that overlap with other lymphomas, especially subcutaneous panniculitis-like T cell lymphoma (SPTCL). The recent World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification distinguishes the more aggressive PCGD-TCL from the usually indolent SPTCL, however. We report a 30-year-old woman with an indurated violaceous plaque on the left cheek that had been present for several years. Biopsies showed a dense lymphocytic infiltrate involving the subcutis and dermis that consisted mostly of small and medium-sized lymphocytes, some with irregular nuclear contours and dense chromatin. These cells were positive for TIA-1, TCR-gamma and CD8, but negative for beta-F1 and granzyme-B. Staging with positron emission tomography-computed tomography (PET/CT), CBC and bone marrow with flow cytometry identified lymphadenopathy as well as blood and marrow involvement by an abnormal TCRgd-positive T-cell proliferation (Ann Arbor Stage IV). The patient's history of a long-standing lesion in this case is unusual, in that gamma-delta T-cell lymphomas are typically rapidly progressive neoplasms. As such, it raises the possibility of 'transformation' of a long-standing inflammatory process into an overt lymphoma.

Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma.

BACKGROUND: Histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. As a result, more sophisticated and objective methods have been sought. The goal of this study was to identify a gene expression signature that reliably differentiated benign and malignant melanocytic lesions and evaluate its potential clinical applicability. Herein, we describe the development of a gene expression signature and its clinical validation using multiple independent cohorts of melanocytic lesions representing a broad spectrum of histopathologic subtypes. METHODS: Using quantitative reverse-transcription polymerase chain reaction (PCR) on a selected set of 23 differentially expressed genes, and by applying a threshold value and weighting algorithm, we developed a gene expression signature that produced a score that differentiated benign nevi from malignant melanomas. RESULTS: The gene expression signature classified melanocytic lesions as benign or malignant with a sensitivity of 89% and a specificity of 93% in a training cohort of 464 samples. The signature was validated in an independent clinical cohort of 437 samples, with a sensitivity of 90% and specificity of 91%. CONCLUSIONS: The performance, objectivity, reliability and minimal tissue requirements of this test suggest that it could have clinical application as an adjunct to histopathology in the diagnosis of melanocytic neoplasms.

Epithelioid sarcoma resembling benign fibrous histiocytoma.

Epithelioid sarcoma (ES) is a rare malignancy notorious for its tendency to histologically mimic granuloma annulare and other palisading granulomatous processes. We report a case of ES on the right hand of a 23-year-old man that histopathologically resembled a benign fibrous histiocytoma. Superficial portions of the tumor were well differentiated, exhibiting spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles. More obvious atypia including greater cellularity, nuclear pleomorphism, and mitotic activity were mostly confined to the deep-seated regions of the tumor. In addition to palisading granulomatous processes, ES can mimic benign fibrous histiocytoma, and the superficial portions of ES may appear deceptively benign.

Soft-tissue myxomatous lesions: review of salient imaging features with pathologic comparison.

Myxoid soft-tissue lesions are a heterogeneous group of benign and malignant mesenchymal tumors with an abundance of extracellular mucoid material. These lesions may mimic cysts on radiologic evaluation because of the high water content, and histopathologic features also overlap. Benign myxoid lesions include intramuscular myxoma, synovial cyst, bursa, ganglion, and benign peripheral nerve sheath tumor, including neurofibroma and schwannoma. Malignant entities include myxoid liposarcoma, myxoid leiomyosarcoma, myxoid chondrosarcoma, ossifying fibromyxoid tumor, and myxofibrosarcoma. Some syndromes are associated with myxoid soft-tissue lesions, such as Mazabraud syndrome in patients with soft-tissue myxomas and fibrous dysplasia. Certain discriminating features, such as intralesional fat in a myxoid liposarcoma, perilesional edema and a rim of fat in soft-tissue myxoma, and the swirled T2-weighted signal intensity and enhancement pattern of aggressive angiomyxoma, assist the radiologist in differentiating these lesions. The presence of an internal chondroid matrix or incomplete peripheral ossification may suggest myxoid chondrosarcoma or ossifying fibromyxoid tumor, respectively. The entering-and-exiting-nerve sign is suggestive of a peripheral nerve sheath tumor. Communication with a joint or tendon sheath and peripheral enhancement may indicate a ganglion or synovial cyst. This article (a) reviews the magnetic resonance, computed tomographic, and ultrasonographic imaging characteristics of soft-tissue myxomatous lesions, emphasizing imaging findings that can help differentiate benign and malignant lesions; (b) presents differential diagnoses; and (c) provides pathologic correlation.

Skin Cancer Risk Is Increased by Somatic Mutations Detected Noninvasively in Healthy-Appearing Sun-Exposed Skin.

Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10-6) and made a more significant contribution than skin tone. Calculations of skin cancer risk matched the known United States population prevalence, indicating that DNA-Skin Cancer Assessment of Risk was well-calibrated. In conclusion, somatic mutations in healthy-appearing sun-exposed skin increase skin cancer risk, and mutations capture risk information that is not accounted for by other risk factors. Clinical utility is supported by the noninvasive nature of skin sample collection through adhesive patches.

Giant cell angiofibroma or localized periorbital lymphedema?

Giant cell angiofibroma represents a rare soft tissue neoplasm with a predilection for the orbit. We recently encountered a mass removed from the lower eyelid of a 56-year-old female that histopathologically resembled giant cell angiofibroma. The process consisted of haphazardly arranged CD34-positive spindled and multinucleated cells within an edematous, densely vascular stroma. However, the patient had recently undergone laryngectomy and radiotherapy for a laryngeal squamous cell carcinoma. A similar mass had arisen on the contralateral eyelid, and both had developed several months post-therapy. Lymphedema of the orbit can present as tumor-like nodules and in some cases may share histopathologic features purported to be characteristic of giant cell angiofibroma. A relationship between giant cell angiofibroma and lymphedema has not been established, but our case suggests there may be one. The potential overlap of these two conditions should be recognized, as should other entities that may enter the differential diagnosis.

Expression of CK7, Cam 5.2 and Ber-Ep4 in cutaneous squamous cell carcinoma.

BACKGROUND: Cytokeratin 7 (CK7) and Cam 5.2 are often used to differentiate extramammary Paget's disease (EPD) from squamous cell carcinoma (SCC) in situ because they are generally considered to be expressed in the former but not in the latter. However, we have encountered CK7+ and Cam 5.2+ SCCs. METHODS: We evaluated CK7, Cam 5.2 and Ber-Ep4 expression in SCC and EPD. RESULTS: We found significant CK7 and Cam 5.2 positivity in SCCs, particularly in those with a pagetoid pattern. Only one case expressed Ber-Ep4. CONCLUSIONS: We conclude that CK7 and Cam 5.2 expression may occur in SCC. A panel including Ber-Ep4 is advisable for immunohistochemical differentiation of EPD from SCC.

Dermal dendritic cells in psoriasis, nummular dermatitis, and normal-appearing skin.

BACKGROUND: The reason psoriasis (PSO) favors extensor skin is unknown. We hypothesized that PSO may involve extensor skin preferentially because of differences in the number or type of dermal dendritic cells (dDCs) between flexural and extensor skin. OBJECTIVE: We sought to compare dDC type and distribution in normal-appearing flexural and extensor skin, PSO, and nummular dermatitis (ND). METHODS: Using immunohistochemical markers, the number, distribution, and type of Langerhans cells, myeloid dendritic cells (DCs), and plasmacytoid DCs was compared in normal-appearing skin, PSO, and ND. RESULTS: Significant differences in dDC density were not identified between flexural and extensor skin, although extensor skin contained fewer CD11a(+) and CD11c(+) cells. Compared with normal-appearing skin, cells expressing CD11a, CD11c, CD123, CD303, and CD207 were increased in PSO. ND lesions showed similar increases. No significant difference between PSO and ND was evident with the exception of decreased S100A6(+) cells in PSO. LIMITATIONS: We did not study seasonal variation in DC density or assess nonlesional skin from patients with PSO. CONCLUSIONS: The data did not support the hypothesis that PSO favors extensor skin because of differences in DC localization. However, dDCs were significantly increased in PSO by comparison with normal-appearing skin, supporting existing evidence that they are involved in the overall pathogenesis of PSO.

Basal cell carcinoma characteristics as predictors of depth of invasion.

BACKGROUND: Pretreatment risk stratification of basal cell carcinoma (BCC) is largely based on histologic subtype reported from biopsy specimens. OBJECTIVE: We sought to determine the degree of concordance between characteristics identified on biopsy specimen and excision and to determine if histologic characteristics other than subtype correlated with depth of invasion. METHODS: Histologic specimens of 100 BCC biopsy specimens and corresponding excisions were reviewed. Anatomic site, histologic subtype, maximum depth of extension, contour of the lobules at the leading edge, elastosis characteristics, presence of necrosis, calcification, and ulceration were recorded. Concordance between biopsy specimens and their excisions with relation to depth of tumor lobules was analyzed. RESULTS: The concordance between the subtype of biopsy specimen and excision was 62%. Micronodular tumors had the greatest mean depth, followed by infiltrative, nodular, and superficial subtypes. Subtype reported from biopsy specimen (P = .0002) and excision (P < .0001) correlated to depth and was superior to age, contours of excision specimens, the presence of necrosis, and the extent of excisional solar elastosis. Gender, anatomic site, contours of biopsy specimens, elastosis color, elastosis type, the presence of ulceration, and calcification did not correlate with depth. LIMITATIONS: Selection bias is present as only standard excisions were included; BCCs treated by other methods were not examined. CONCLUSIONS: BCC subtype identified on biopsy specimen may not correlate with subtype identified on excision. Morphologic subtype has the highest correlation with depth and reporting should reflect the highest risk growth pattern if a biopsy specimen contains more than one pattern. Consideration should be given to reporting necrosis and degree of solar elastosis.

Robust activation of the human but not mouse telomerase gene during the induction of pluripotency.

Pluripotent stem cells (PSCs) express telomerase and have unlimited proliferative potential. To study telomerase activation during reprogramming, 3 classes of embryonic stem cell (ESC)-like clones were isolated from mouse fibroblasts containing a transgenic hTERT reporter. Class I expressed few pluripotency markers, whereas class II contained many, but not Oct4, Nanog, and Sox2. Neither class of cells differentiated efficiently. Class III cells, the fully reprogrammed induced PSCs (iPSCs), expressed all pluripotency markers, formed teratomas indistinguishable from those of mESCs, and underwent efficient osteogenic differentiation in vitro. Interestingly, whereas the endogenous mTERT gene expression was only moderately increased during reprogramming, the hTERT promoter was strongly activated in class II cells and was further elevated in class III cells. Treatment of class II cells with chemical inhibitors of MEKs and glycogen synthase kinase 3 resulted in their further reprogramming into class III cells, accompanied by a strong activation of hTERT promoter. In reprogrammed human cells, the endogenous telomerase level, although variable among different clones, was dramatically elevated. Only in cells with the highest telomerase were telomeres restored to the lengths in hESCs. Our data, for the first time, demonstrated that the hTERT promoter was strongly activated in discrete steps, revealing a critical difference in human and mouse cell reprogramming. Because telomere elongation is crucial for self-renewal of hPSCs and replicative aging of their differentiated progeny, these findings have important implications in the generation and applications of iPSCs.

Persistent melanocytic nevi: a review and analysis of 205 cases.

BACKGROUND: Melanocytic nevi can recur or persist if not completely excised and are capable of mimicking malignant melanoma, both clinically and histologically. OBJECTIVE: To characterize the impact of anatomic site, biopsy method, size, margin involvement and type of original melanocytic nevus on recurrence/persistence of melanocytic nevi. Secondarily, we sought to determine if the original type of melanocytic nevus could be determined solely from microscopic examination of the recurrent/persistent nevus. METHODS: One hundred and eighty-five patients with 205 persistent nevi were identified. Of these, 108 cases had original biopsy specimens available for review. Location, original biopsy size, biopsy method, margins and interval to recurrence were recorded for each. A group of 232 non-persistent nevi was established as a control population. RESULTS: There was a female predominance in persistent nevi with the back being the most common site for persistence. Dysplastic melanocytic nevi were the most likely to persist. Accurate determination of the original type of melanocytic nevus from microscopic examination of the persistent nevus was possible in only 67% of the cases. CONCLUSION: Clinicians should take larger and deeper biopsies of clinically dysplastic and conventional melanocytic nevi on the back to prevent recurrences. Grading atypia of the persistent melanocytic nevi is unreliable.

Clinical Use of a Diagnostic Gene Expression Signature for Melanocytic Neoplasms.

A gene expression signature has been validated as an adjunct to traditional methods of differentiating malignant and benign melanocytic neoplasms, and its use in clinical practice warrants further study. This study followed patients whose melanocytic neoplasms were managed according to a benign result from the gene expression signature (N=25). Eligible patients whose tested lesions were classified as benign by the gene expression signature and were subsequently treated as benign by their dermatology providers were observed for a mean follow-up period of 38.5 months. Results suggest that many patients with melanocytic neoplasms classified as benign by the gene expression signature may safely forego additional surgical excision.

CD10-positive myxofibrosarcomas: a pitfall in the differential diagnosis of atypical fibroxanthoma.

CD10 is now commonly used to differentiate atypical fibroxanthoma (AFX) from melanoma, spindle cell and dedifferentiated variants of squamous cell carcinoma and leiomyosarcoma. However, we have encountered CD10-positive tumors that mimicked AFX but proved to be myxofibrosarcomas. The purpose of this study was to evaluate CD10 expression in a wide range of mesenchymal neoplasms that may involve the skin using tissue microarrays. Our results indicate that in addition to AFX, CD10 expression is common in myxofibrosarcomas, undifferentiated pleomorphic sarcomas, dermatofibromas and dermatofibrosarcoma protuberans. Myxofibrosarcomas commonly present in the skin and may be difficult to distinguish from AFX on small biopsies and CD10 positivity may confound the diagnostic difficulty.

Multiple cutaneous monoclonal B-cell proliferations as harbingers of systemic angioimmunoblastic T-cell lymphoma.

We describe a 66-year-old man initially diagnosed with primary cutaneous marginal zone B-cell lymphoma who developed four additional monoclonal/monotypic B-cell lymphoid proliferations and a systemic angioimmunoblastic T-cell lymphoma over the course of 19 months. Through retrospective analysis, we identified the evolution of a T-cell clone within the background of clinically and pathologically dominant cutaneous B-cell tumors. In terms of clinical practice, this case supports that patients diagnosed with multiple clonal B-cell proliferation need thorough investigation and close clinical follow up to identify a coexistent or evolving systemic lymphoma, in particular, peripheral T-cell lymphomas of follicular T-helper cell type, such as angioimmunoblastic T-cell lymphoma. Biologically, this case offers unique insight into the interactions between B-cell and T-cell lineages in lymphoid neoplasia.