Jonhan Ho

Diagnostic Inaccuracy of Smartphone Applications for Melanoma Detection

OBJECTIVE To measure the performance of smartphone applications that evaluate photographs of skin lesions and provide the user with feedback about the likelihood of malignancy. DESIGN Case-control diagnostic accuracy study. SETTING Academic dermatology department. PARTICIPANTS AND MATERIALS: Digital clinical images of pigmented cutaneous lesions (60 melanoma and 128 benign control lesions) with a histologic diagnosis rendered by a board-certified dermatopathologist, obtained before biopsy from patients undergoing lesion removal as a part of routine care. MAIN OUTCOME MEASURES Sensitivity, specificity, and positive and negative predictive values of 4 smartphone applications designed to aid nonclinician users in determining whether their skin lesion is benign or malignant. RESULTS Sensitivity of the 4 tested applications ranged from 6.8% to 98.1%; specificity, 30.4% to 93.7%; positive predictive value, 33.3% to 42.1%; and negative predictive value, 65.4% to 97.0%. The highest sensitivity for melanoma diagnosis was observed for an application that sends the image directly to a board-certified dermatologist for analysis; the lowest, for applications that use automated algorithms to analyze images. CONCLUSIONS The performance of smartphone applications in assessing melanoma risk is highly variable, and 3 of 4 smartphone applications incorrectly classified 30% or more of melanomas as unconcerning. Reliance on these applications, which are not subject to regulatory oversight, in lieu of medical consultation can delay the diagnosis of melanoma and harm users.

Importance of glycolysis and oxidative phosphorylation in advanced melanoma

Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.

Human Polyomavirus 7–Associated Pruritic Rash and Viremia in Transplant Recipients

Human polyomavirus 7 (HPyV7) is one of 11 HPyVs recently discovered through genomic sequencing technologies. Two lung transplant recipients receiving immunosuppressive therapy developed pruritic, brown plaques on the trunk and extremities showing a distinctive epidermal hyperplasia with virus-laden keratinocytes containing densely packed 36-45-nm icosahedral capsids. Rolling circle amplification and gradient centrifugation testing were positive for encapsidated HPyV7 DNA in skin and peripheral blood specimens from both patients, and HPyV7 early and capsid proteins were abundantly expressed in affected tissues. We describe for the first time that HPyV7 is associated with novel pathogenicity in some immunosuppressed individuals.

Feature-preserving artifact removal from dermoscopy images

Dermoscopy, also called surface microscopy, is a non-invasive imaging procedure developed for early screening of skin cancer. With recent advance in skin imaging technologies and image processing techniques, there has been increasing interest in computer-aided diagnosis of skin cancer from dermoscopy images. Such diagnosis requires the identification of over one hundred cutaneous morphological features. However, computer procedures designed for extracting and classifying these intricate features can be distracted by the presence of artifacts like hair, ruler markings, and air bubbles. Therefore, reliable artifact removal is an important pre-processing step for improving the performance of computer-aided diagnosis of skin cancer. In this paper, we present a new scheme that automatically detects and removes hairs and ruler markings from dermoscopy images. Moreover, our method also addresses the issue of preserving morphological features during artifact removal. The key components of this method include explicit curvilinear structure detection and modeling, as well as feature guided exemplar-based inpainting. We experiment on a number of dermoscopy images and demonstrate that our method produces superior results compared to existing techniques.

Use of contextual inquiry to understand anatomic pathology workflow: Implications for digital pathology adoption.

Background: For decades anatomic pathology (AP) workflow have been a highly manual process based on the use of an optical microscope and glass slides. Recent innovations in scanning and digitizing of entire glass slides are accelerating a move toward widespread adoption and implementation of a workflow based on digital slides and their supporting information management software. To support the design of digital pathology systems and ensure their adoption into pathology practice, the needs of the main users within the AP workflow, the pathologists, should be identified. Contextual inquiry is a qualitative, user-centered, social method designed to identify and understand users′ needs and is utilized for collecting, interpreting, and aggregating in-detail aspects of work. Objective: Contextual inquiry was utilized to document current AP workflow, identify processes that may benefit from the introduction of digital pathology systems, and establish design requirements for digital pathology systems that will meet pathologists′ needs. Materials and Methods: Pathologists were observed and interviewed at a large academic medical center according to contextual inquiry guidelines established by Holtzblatt et al. 1998. Notes representing user-provided data were documented during observation sessions. An affinity diagram, a hierarchal organization of the notes based on common themes in the data, was created. Five graphical models were developed to help visualize the data including sequence, flow, artifact, physical, and cultural models. Results: A total of six pathologists were observed by a team of two researchers. A total of 254 affinity notes were documented and organized using a system based on topical hierarchy, including 75 third-level, 24 second-level, and five main-level categories, including technology, communication, synthesis/preparation, organization, and workflow. Current AP workflow was labor intensive and lacked scalability. A large number of processes that may possibly improve following the introduction of digital pathology systems were identified. These work processes included case management, case examination and review, and final case reporting. Furthermore, a digital slide system should integrate with the anatomic pathologic laboratory information system. Conclusions: To our knowledge, this is the first study that utilized the contextual inquiry method to document AP workflow. Findings were used to establish key requirements for the design of digital pathology systems.

Development and validation of a noninvasive 2-gene molecular assay for cutaneous melanoma

Background: Clinical and histopathologic assessment of pigmented skin lesions remains challenging even for experts. Differentiated and accurate noninvasive diagnostic modalities are highly desirable. Objective: We sought to provide clinicians with such a tool. Methods: A 2‐gene classification method based on LINC00518 and preferentially expressed antigen in melanoma (PRAME) gene expression was evaluated and validated in 555 pigmented lesions (157 training and 398 validation samples) obtained noninvasively via adhesive patch biopsy. Results were compared with standard histopathologic assessment in lesions with a consensus diagnosis among 3 experienced dermatopathologists. Results: In 398 validation samples (87 melanomas and 311 nonmelanomas), LINC00518 and/or PRAME detection appropriately differentiated melanoma from nonmelanoma samples with a sensitivity of 91% and a specificity of 69%. We established LINC00518 and PRAME in both adhesive patch melanoma samples and underlying formalin fixed paraffin embedded (FFPE) samples of surgically excised primary melanomas and in melanoma lymph node metastases. Limitations: This technology cannot be used on mucous membranes, palms of hands, and soles of feet. Conclusions: This noninvasive 2‐gene pigmented lesion assay classifies pigmented lesions into melanoma and nonmelanoma groups and may serve as a tool to help with diagnostic challenges that may be inherently linked to the visual image and pattern recognition approach. Graphical abstract: Figure. No Caption available.

Melanoma depth in patients with an established dermatologist

BACKGROUND The impact of having an established dermatologist on melanoma depth at diagnosis is incompletely understood. OBJECTIVE We sought to determine whether having had a previous dermatologic examination (an established dermatologist), the recency of the last examination, and the wait time for the dermatology appointment are associated with melanoma invasiveness and depth. METHODS This was a retrospective cross-sectional study of 388 patients with primary melanoma at an academic dermatology department. RESULTS Patients with an established dermatologist were more likely than patients without an established dermatologist to be given a diagnosis of melanoma in situ (103/162 [63.6%] vs 69/155 [44.5%], P = .001) and to have thinner invasive melanoma (0.48 [0.30-0.71] mm vs 0.61 [0.40-1.10] mm, respectively, P = .003). These trends were observed for patients with self-detected, but not dermatologist-detected, melanoma. Patient-detected melanomas made up 184/361 (51.0%) of all melanomas, 83/199 (41.7%) of in situ melanomas, and 101/162 (62.4%) invasive melanomas. Self-detected melanomas were in situ in 36 of 61 (59.0%) patients with an established dermatologist versus 40 of 108 (37.0%) patients without an established dermatologist, P = .006. Neither time from last dermatologic examination nor wait time for an appointment was associated with melanoma invasiveness or depth. LIMITATIONS Data are retrospective and from 1 large academic health care system. CONCLUSION Education obtained at the dermatology appointment may improve early self-detection of melanoma, and having an established dermatologist may facilitate earlier evaluation of concerning lesions.

Dysplastic nevi with severe atypia: Long-term outcomes in patients with and without re-excision

Background: Dysplastic nevi with severe atypia (severely dysplastic nevi [SDN]) are frequently re‐excised because of the concern that these lesions may in fact represent early melanoma. Data on long‐term follow‐up of these patients are limited. Objective: We sought to determine the rate of subsequent melanoma development in patients with SDN who underwent re‐excision versus those who did not and to determine factors associated with decision to re‐excise. Methods: A retrospective single institutional study was conducted with 451 adult patients (mean age 41.3 years) with SDN biopsied between November 1994 and November 2004, with clinical follow‐up of at least 5 years. Results: In 451 patients with SDN, re‐excision was performed on 36.6%. Two melanomas were diagnosed in the re‐excision specimens. Subsequent metastatic melanoma developed in 7 patients, all of whom had a history of melanoma. Margin comments influenced decision to re‐excise. Limitations: This was a retrospective study at a single institution. Conclusion: Re‐excision of all SDN may not be necessary.

Langerhans cell histiocytosis and Erdheim-Chester disease, both with cutaneous presentations, and papillary thyroid carcinoma all harboring the BRAF(V600E) mutation.

Langerhans cell histocytosis (LCH) and Erdheim‐Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38‐year‐old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non‐LCH xanthogranuloma type lesion. BRAFV600E mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim‐Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAFV600E mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAFV600E mutation in a non‐LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim‐Chester disease workup. This is a unique case of a woman with BRAFV600E mutation positive Erdheim‐Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAFV600E mutation positive papillary thyroid carcinoma.

Primary cutaneous endocrine mucin-producing sweat gland carcinoma co-occurring simultaneously with low-grade ductal mucinous breast cancer: a clinicopathologic conundrum.

To the Editor: Endocrine mucin–producing sweat gland carcinoma (EMPSGC) is a rare, underreported, low-grade cutaneous malignancy affecting elderly patients with a median age of 70 years, and a significant predilection for females. The tumor typically occurs on the eyelids or periorbital skin and manifests clinically as a nondescript slowly enlarging flesh-colored nodule, plaque, or swelling. Histologically, it is characterized by low-grade morphological features, production of mucin, and expression of neuroendocrine markers. The tumor is clinically indolent and cured by local excision; however, local recurrences may occur. The coexistence of EMPSGC and low-grade ductal mucinous breast carcinoma has not been hitherto reported. A 75-year-old white female with no oncologic history presented to her dermatologist with a small, asymptomatic, nonulcerated, skin-colored nodule located on the skin adjacent to her left lower eyelid, and slowly enlarging over a period of approximately 3 years. The initial pathologic interpretation at an outside institution was of poorly differentiated carcinoma, and a metastasis was favored. The patient requested a second opinion. Our microscopic examination of the excisional biopsy revealed a well-demarcated dermal tumor composed of solid and focal cribriform nests and strands separated by thin fibrous septa. The nests consisted of medium sized round to oval cells with relatively monomorphic nuclei and amphophilic cytoplasm embedded in a mucinous stroma (Figs. 1A–C). Occasional intracellular mucin and hyalinized fibrovascular cores were noted. The tumor cells were positive for cytokeratin AE1/AE3, estrogen and progesterone receptors, GCDFP15, cytokeratin 7, and patchy for synaptophysin (Figs. 1E, F), whereas negative for cytokeratin 20, CDX-2, and S100. There was no immunohistochemical evidence of Her2/neu overexpression. Ki-67 proliferation index ranged from 5% to 10%. P63 and calponin revealed a layer of myoepithelial cells at the periphery of some tumor nests, indicating an in situ component (Fig. 1D). Based on morphological and immunohistochemical features, the tumor was reclassified as a primary cutaneous EMPSGC. Although a primary cutaneous malignancy was favored, given the demographics of the patient, screening for breast cancer was suggested. Subsequent imaging showed a left breast mass that was biopsied and excised to reveal a 2.8 cm welldifferentiated invasive ductal mucinous carcinoma (Nottingham grade 1) with a focal in situ component (Figs 2A–C). The tumor showed a diffuse expression of estrogen and progesterone receptors,