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.

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.

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.

The California Telepathology Service: UCLA's Experience in Deploying a Regional Digital Pathology Subspecialty Consultation Network.

BACKGROUND: The need for extending pathology diagnostic expertise to more areas is now being met by the maturation of technology that can effectively deliver this level of care. The experience and lessons learned from our successfully deployed International Telepathology Service (ITS) to a hospital system in China guided us in starting a domestic telepathology network, the California Telepathology Service (CTS). Many of the lessons learned from the ITS project informed our decision-making for the CTS. New challenges were recognized and overcome, such as addressing the complexity and cost-benefit tradeoffs involved in setting up a digital consultation system that competes with an established conventional glass slide delivery system. METHODS: The CTS is based on a hub-and-spoke telepathology network using Leica Biosystems whole-slide image scanners and the eSlide Manager (eSM Version 12.3.3.7055, Leica Biosystems) digital image management software solution. The service currently comprises six spoke sites (UC San Diego [UCSD], UC Irvine [UCI], UC Davis, Northridge Hospital Medical Center [NHMC], Olive View Medical Center [OVMC], and Children's Hospital Los Angeles) and one central hub site (UCLA Medical Center). So far, five sites have been validated for telepathology case consultations following established practice guidelines, and four sites (UCI, UCSD, NHMC, and OVMC) have activated the service. RESULTS: For the active spoke sites, we reviewed the volume, turnaround time (TAT), and case types and evaluated for utility and value. From May 2017 to July 2018, a total of 165 cases were submitted. Of note, digital consultations were particularly advantageous for preliminary kidney biopsy diagnoses (avg TAT 0.7 day). CONCLUSION: For spoke sites, telepathology provided shortened TAT and significant financial savings over hiring faculty with expertise to support a potentially low-volume service. For the hub site, the value includes exposure to educationally valuable cases, additional caseload volume to support specialized services, and improved communication with referring facilities over traditional carrier mail. The creation of a hub-and-spoke telepathology network is an expensive undertaking, and careful consideration needs to be given to support the needs of the clinical services, acquisition and effective deployment of the appropriate equipment, network requirements, and laboratory workflows to ensure a successful and cost-effective system.

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.

Secretory Carcinoma of the Skin Harboring ETV6 Gene Fusions: A Cutaneous Analogue to Secretory Carcinomas of the Breast and Salivary Glands.

Mammary analogue secretory carcinoma is a low-grade salivary gland carcinoma that exhibits analogous features to secretory carcinoma of the breast including the presence of a t(12;15) translocation resulting in the ETV6-NTRK3 gene fusion. Rare cases of purported secretory carcinoma of the skin adnexa have been reported, but their relationship to true secretory carcinoma of the breast and salivary glands is unclear, as they generally do not harbor ETV6 rearrangements. Cases of cutaneous neoplasms with histologic features identical to secretory carcinoma of the breast and salivary glands were identified from the consultation files of 3 academic medical institutions. Immunohistochemistry was performed for S100 protein, mammaglobin and STAT5a. Break-apart fluorescence in situ hybridization was used evaluate for disruption of the ETV6 gene. Six cases of cutaneous secretory carcinoma were identified. The tumors arose in 4 women and 2 men, ranging from 24 to 71 years in age (mean, 47 y). The carcinomas presented in the skin of the axilla (n=4), ventral neck (n=1), and cheek (n=1). The tumors arose in the superficial dermis in association with adnexal structures. None of the patients had a prior or concurrent breast or salivary gland tumor. They were histologically characterized by well-circumscribed but unencapsulated proliferations of bland, eosinophilic cells arranged in microcysts and follicles with intraluminal secretions. Ectopic breast or salivary gland tissue was not identified. The cases were diffusely positive for S100 protein (6 of 6), mammaglobin (6 of 6), and STAT5a (5 of 5). All 6 cases harbored rearrangements of ETV6. All tumors were treated by simple excision alone. No recurrences or metastases developed in the 2 cases with follow-up. Secretory carcinoma of the skin represents a phenotypic, immunohistochemical, and genetic counterpart to secretory carcinoma of the breast and salivary glands. This tumor entity is less anatomically restricted than previously supposed.

RadPath: A Web-based System for Integrating and Correlating Radiology and Pathology Findings During Cancer Diagnosis.

RATIONALE AND OBJECTIVES: The current paradigm of cancer diagnosis involves uncoordinated communication of findings from radiology and pathology to downstream physicians. Discordance between these findings can require additional time from downstream users to resolve, or given incorrect resolution, may adversely impact treatment decisions. To mitigate this problem, we developed a web-based system, called RadPath, for correlating and integrating radiology and pathology reporting. MATERIALS AND METHODS: RadPath includes interfaces to our institution's clinical information systems, which are used to retrieve reports, images, and test results that are structured into an interactive compendium for a diagnostic patient case. The system includes an editing interface for physicians, allowing for the inclusion of additional clinical data, as well as the ability to retrospectively correlate and contextualize imaging findings following pathology diagnosis. RESULTS: During pilot deployment and testing over the course of 1 year, physicians at our institution have completed 60 RadPath cases, requiring an average of 128 seconds from a radiologist and an average of 93 seconds from a pathologist per case. Several technical and workflow challenges were encountered during development, including interfacing with diverse clinical information systems, automatically structuring report contents, and determining the appropriate physicians to create RadPath summaries. Reaction to RadPath has been positive, with users valuing the system's ability to consolidate diagnostic information. CONCLUSIONS: With the increasing complexity of medicine and the movement toward team-based disease management, there is a need for improved clinical communication and information exchange. RadPath provides a platform for generating coherent and correlated diagnostic summaries in cancer diagnosis with minimal additional effort from physicians.

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.

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.

Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.

Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.

Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma".

Melanotic schwannomas (MSs), variably associated with the Carney complex, are rare tumors that usually involve spinal nerve roots but may occur in other locations. Clinicopathologic evaluation poorly predicts the behavior of MS. Fewer than 200 cases have been reported. We report a series of 40 well-characterized MSs, one of the largest series to date. The tumors were comprehensively evaluated, and clinical follow-up was obtained. Immunohistochemistry for S100 protein, Melan-A, HMB45, tyrosinase, glial fibrillary acidic protein (GFAP), EMA, SMARCB1, Ki-67 antigen, ASMTL, and the Carney complex-associated PRKAR1A gene product was performed using commercially available antibodies and the Ventana Ultraview detection system. Gene microarray study was conducted on formalin-fixed, paraffin-embedded blocks from 10 MSs and the results compared with previous data from melanoma and schwannoma. Differentially expressed genes were selected at >3-fold and P<0.001. The Fisher exact test was used for statistical analysis. The tumors occurred in 18 male and 22 female patients (mean age 41 y; range, 11 to 84 y) and involved the paravertebral nerve roots (N=31), mediastinum (N=3), sacrum, cauda equina, para-aortic region, fifth cranial nerve, buttock, and cerebellum (N=1 each). Two patients had known Carney complex, and 1 patient also had a cutaneous myxoma, suggestive of Carney complex. The tumors expressed S100 protein (21/25, 84%), Melan-A (23/25, 92%), HMB45 (25/25, 100%), tyrosinase (25/25, 100%), GFAP (0/24, 0%), EMA (0/9, 0%), SMARCB1 (retained in 25/25, 100%), and ASMTL (5/19, 26%); PRKAR1A expression was lost in 7/20 cases (35%). Ki-67-labeling index was <5% in 23/25 cases (92%) and 5% to 10% in 2/25 cases (8%). Gene expression profiling showed significant differences between MS, melanoma, and conventional schwannoma. Clinical follow-up (26/40, 65%; mean 55 mo; range, 1 to 300 mo) showed local recurrences in 9/26 (35%) and metastases in 11/26 (44%) patients. Fourteen patients were alive without disease, 5 were alive with disease, and 7 had died of disease. Only a mitotic rate >2/10 HPF correlated with metastases (P=0.008). The clinicopathologic features of tumors with and without psammoma bodies were identical. We conclude that MSs are distinctive malignant tumors, rather than benign neoplasms with occasionally unpredictable behavior, and propose their reclassification as "malignant melanotic schwannian tumors." Loss of PRKAR1A expression suggests a link to Carney complex, even when this history is absent.

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.

Cytogenetics of melanoma: a review.

Malignant melanoma is an aggressive cutaneous neoplasm whose incidence has continued to increase worldwide. Currently, histopathologic examination of specimens is the gold standard for the diagnosis and categorization of melanoma. Cytogenetic analysis represents a powerful, and currently underused, adjunct to traditional histologic examination in distinguishing nevi and melanomas. Chromosomal studies have shown that malignant melanomas often contain multiple chromosomal alterations, most commonly of chromosomes 1, 6, 7, 9, 10 and 11. These chromosomes often include genes within the MAPK molecular pathway, which is involved in the development and progression of melanoma. Fluorescence in situ hybridization (FISH) can detect a number of recurrent anomalies, and commercially available kits for melanoma detection have been devised. The utility of cytogenetics in melanocytic lesions at certain anatomic sites has been evaluated, including acral lesions, uveal lesions, and lymph node metastases. Recurring cytogenetic anomalies have been defined in various challenging histologic subtypes, such as desmoplastic melanomas and Spitzoid lesions. Cytogenetic analysis may also be used to provide supplementary information in prognostication, particularly in uveal melanomas. We provide a brief review of the molecular pathways found in melanoma and a summary of what is known and remains unknown regarding cytogenetic aberrations associated with malignant melanoma.

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.