Thaddeus W. Mully

Endovascular stenting of an acutely thrombosed basilar artery: technical case report and review of the literature.

OBJECTIVE AND IMPORTANCE The goal of this report was to describe the successful percutaneous endovascular use of a Gianturco-Roubin-2 coronary stent in the treatment of an acute atherothrombotic occlusion of the basilar artery. To our knowledge, the percutaneous endovascular deployment of an intra-arterial stent for the treatment of an acute atherothrombotic occlusion of the basilar artery and the percutaneous endovascular placement of a Gianturco-Roubin-2 stent in the basilar artery have not been previously reported. CLINICAL PRESENTATION An 83-year-old man presented with a recurrent, transient, locked-in syndrome resulting from a lower basilar artery occlusion caused by vertebrobasilar thrombosis superimposed on severe proximal basilar artery atheromatous stenosis. INTERVENTION After successful superselective intra-arterial thrombolysis of the vertebrobasilar clot, balloon angioplasty of the underlying basilar artery stenosis was performed, without significant angiographic improvement. Percutaneous endovascular deployment of a Gianturco-Roubin-2 coronary stent of 4-mm diameter was subsequently performed, with excellent angiographic results. CONCLUSION The patient made a very good neurological recovery but unfortunately died as a result of cardiogenic shock and sepsis. Detailed neuropathological follow-up results are presented; stent patency was revealed in the postmortem examination. The anatomic and pathophysiological considerations of basilar artery stent placement for the treatment of acute basilar artery occlusion related to atherosclerotic stenosis are discussed.

Activating MET kinase rearrangements in melanoma and Spitz tumours

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K), and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

Ambiguous Melanocytic Tumors with loss of 3p21

Germline loss-of-function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi. Similar melanocytic tumors occurring in a sporadic setting have been demonstrated to have biallelic loss of BAP1. In some of these sporadic tumors, loss of BAP1 occurs through mutation of 1 allele and genomic loss of the other. We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus. The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population. We further characterized the BAP1 status in 17 of these tumors with available additional material, confirming loss of BAP1 in all cases. We describe BAP1 loss in a blue nevus–like melanoma and further expand the histopathologic spectrum of spitzoid melanocytic neoplasms with BAP1 loss.

Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions.

Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.

The 7th edition AJCC staging system for cutaneous squamous cell carcinoma accurately predicts risk of recurrence for heart and lung transplant recipients.

BACKGROUND Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy after solid organ transplantation, with an increased risk of recurrence and metastasis over the general population. The newly updated 7th edition American Joint Committee on Cancer (AJCC) staging system for cSCC is based on consensus expert opinion and requires validation in large cohort studies and in specific patient subpopulations. OBJECTIVE Our objective was to evaluate the risk of cSCC recurrence in a high-risk population of heart and lung transplant recipients, based on the 7th edition AJCC staging system. METHODS We performed a 10-year retrospective cohort study of all primary cSCC diagnosed in heart and lung transplant recipients at a tertiary care academic dermatology center. RESULTS The cumulative incidence of local recurrence was 4% for cSCC in situ and 19% for stage I cSCC at 5 years, and 54% for stage II cSCC at 3 years. Stage II tumors had a 10-fold greater risk of recurrence than stage I, and a 43-fold greater risk of recurrence than in situ tumors. LIMITATIONS This study is limited to a specific patient subgroup at a tertiary care center, and may not be generalizable to all populations. CONCLUSIONS Heart and lung transplant recipients are at high risk for local recurrence of cSCC. These data substantiate the prognostic accuracy of the newly updated 7th edition AJCC staging system for stage 0, I, and II cSCC in this population and demonstrate the aggressive behavior of this cancer in immunosuppressed patients.

Alpha-interferon induced sarcoidosis mimicking metastatic melanoma

Despite its modest potential benefit, alpha‐interferon is one of the most frequently employed therapies for melanoma. With the increasing incidence of melanoma, a parallel increase in interferon use and the associated adverse reactions that accompany interferon therapy should be expected. We present a case of an interferon‐induced sarcoidosis‐like reaction in a melanoma patient that was initially misinterpreted clinically and radiographically as metastatic melanoma. The etiology of sarcoidosis remains a mystery, but appears to involve Th‐1 cytokines such as interferon and interleukin‐2. Observance of a sarcoidosis‐like reaction induced by interferon therapy lends additional support to the importance of this cytokine in the pathogenesis of sarcoidosis. It is important for pathologists to be aware of this entity when interpreting biopsies from melanoma patients treated with interferon.

Basal cell carcinoma on the ear is more likely to be of an aggressive phenotype in both men and women

BACKGROUND We observed that basal cell carcinoma (BCC) on the ear demonstrates a more aggressive phenotype compared with other body sites. OBJECTIVE We sought to determine if it is statistically significant that BCC on the ear is more aggressive. METHODS We queried our 2009 database for all BCCs biopsied from the ear. Multiple data points, including tumor subtype and risk level, were analyzed for 100 BCCs on the ear and 100 BCCs on the cheek. RESULTS BCC on the ear was diagnosed 471 times. Of the first 100 occurrences of BCC on the ear, 57% were high risk compared with 38% on the cheek (odds ratio 2.16, 95% confidence interval 1.23-3.81, P = .01). Men were more likely to have BCC on the ear: 79% male on the ear and 53% male on the cheek (P < .001). However, BCC on the ear in women is also more likely to be aggressive (57%, 12 of 21). LIMITATIONS The data were retrieved from a single year at our institution, and there could potentially be regional bias given that the population of data is from a single institution. Many of the specimens we evaluate are reviewed in consultation and may thus represent a selection bias. CONCLUSION BCC on the ear presents as an aggressive phenotype in the majority of cases for both men and women, and it occurs much more frequently in men. Knowledge of this information can help guide physicians and ensure that these tumors are adequately biopsied and treated.

Reactive eccrine syringofibroadenomatosis secondary to primary cutaneous amyloidosis: a novel association

We report the unprecedented case of reactive eccrine syringofibroadenoma (ESFA) secondary to primary cutaneous amyloidosis. A 62‐year‐old woman of Asian ethnicity presented with a pruritic rash on the back of long‐standing duration. Physical examination revealed diffuse hyperpigmentation localized to the interscapular region; there were a multitude of hyperpigmented macules merged in a rippled pattern intermixed with scattered papules and cobblestone‐like areas. A punch biopsy from a papule was taken. Histopathological examination revealed a network of epithelial strands and cords hanging from the epidermis and harboring foci of ductal differentiation. Eosinophilic collections of amorphous material were found between the epithelial strands, obscuring the superficial dermis. The microscopic picture was consistent with primary cutaneous amyloidosis associated with reactive ESFA. Results of histochemical and immunohistochemical staining confirmed the diagnosis. We speculate that pathogenetic mechanisms intrinsic to primary cutaneous amyloidosis, in addition to unknown genetic factors, resulted in clinical changes of lichen amyloidosus associated with an abnormal hyperplastic epithelial response with histopathological features of ESFA rather than the common epidermal change of acanthosis and hyperkeratosis.

Absence of peripheral blood chimerism in graft-vs-host disease following orthotopic liver transplantation: case report and review of the literature

Graft‐vs‐host disease (GVHD) is a rare and often fatal complication of orthotopic liver transplantation (OLT). The skin is frequently involved early in disease progression, but clinical and histopathological features may be nonspecific, presenting a diagnostic challenge. While the detection of peripheral blood chimerism has been proposed as a diagnostic criterion for post‐OLT GVHD, it is not known whether peripheral blood chimerism is an absolute requirement for the diagnosis.

Transcriptional Programming of Normal and Inflamed Human Epidermis at Single-Cell Resolution

SUMMARY Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, ~12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C+CD301A+ myeloid dendritic cell population in psoriatic epidermis, and IL1βhi CCL3hiCD14+ monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation.