Single-Nucleotide Polymorphism Array for Histologically Ambiguous Melanocytic Tumors.

Genome-wide copy number profiling by single-nucleotide polymorphism (SNP) array is increasingly employed in the clinical diagnostic workup of melanocytic tumors. We present our SNP array results on 675 melanocytic tumors, including 615 histologically ambiguous tumors evaluated by our institution's dermatopathology consultation service and a separate validation cohort of 26 known benign nevi and 34 known malignant melanomas. The total number of somatic copy number abnormalities, sub-chromosomal copy number abnormalities, regions of homozygosity, and abnormalities at disease-associated regions was significantly associated with a diagnosis of malignancy across disease categories. In our study, the number of copy number abnormalities was the factor that best discriminated between benign versus malignant diagnoses, confirming recent published research. Histologically ambiguous tumors had a range and spectrum of abnormalities, including recurrent 11p gains, copy state transitions over kinase genes, and 3p deletions overlapping BAP1 in neoplasms with Spitzoid morphology. Our data suggest that histologically ambiguous melanocytic neoplasms and early primary melanomas have a range of abnormalities that is intermediate between unambiguous benign or malignant melanocytic neoplasms. Careful technical review and an integrated diagnostic approach are essential for the accurate interpretation of SNP array results on histologically ambiguous melanocytic tumors.

Acral localized acquired cutis laxa as presenting sign of underlying systemic amyloidosis.

Acral localized acquired cutis laxa (ALACL) is a rare variant of acquired cutis laxa, and the clinical appearance is characterized by loose, redundant and wrinkled skin of the distal extremities. By definition, histopathology of affected tissue reveals sparse or fragmented elastic fibers. However, this can be difficult to assess on routine staining, and sometimes requires electron microscopy. The condition has been associated with plasma cell dyscrasias or recurrent inflammatory states. We present a case of a 65-year-old man who presented with enlarged and doughy finger pads. Skin biopsy showed diffuse dermal amyloid deposition displacing dermal stroma and reduction of elastic fibers, although these changes were subtle on routine hematoxylin and eosin staining. Mass spectrometry of laser capture microdissected tissue showed AL kappa-type amyloid and further workup revealed a diagnosis of primary systemic AL-kappa amyloidosis requiring bone marrow transplantation. This case represents an unusual presentation of acquired cutis laxa and highlights the need for a high index of suspicion when reviewing histopathology of this entity. In addition, the case highlights the importance of investigation into possible systemic associations, such as plasma cell dyscrasias.

Correlation of novel ALKATI with ALK immunohistochemistry and clinical outcomes in metastatic melanoma.

AIMS: Recently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALKATI ), has been described in melanoma and is susceptible to targeted ALK-inhibitor therapy. Clinical outcomes of patients with ALKATI mutated melanoma as well as correlation with immunohistochemical (IHC) methods have not yet been described. METHODS AND RESULTS: Clinicopathological characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescence in-situ hybridisation and RNA-based digital molecular analysis assays were performed on archival tissue from 173 stage III and 192 stage IV tumours. ALKATI was identified in 12.7 and 4.8% stage III and IV tumours, respectively. Discrete presentations of the ALKATI are seen: isolated ALKATI (n = 20) and mixed ALKATI (combined ALKATI and ALKWT ; n = 7). Isolated ALKWT expression (n = 4) was seen with no ALK fusions. Stage III patients showed improved survival with ALKATI expression compared to those with ALKWT or no expression [5-year survival 80, 95% confidence interval (CI) = 57-100% versus 43%, 95% CI = 34-55%, P = 0.013]. Clinicopathological characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (n = 12) has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALKATI . CONCLUSION: Presence of ALKATI is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALKATI for targeted therapy.

Classification of Melanocytic Lesions in Selected and Whole-Slide Images via Convolutional Neural Networks.

Whole-slide images (WSIs) are a rich new source of biomedical imaging data. The use of automated systems to classify and segment WSIs has recently come to forefront of the pathology research community. While digital slides have obvious educational and clinical uses, their most exciting potential lies in the application of quantitative computational tools to automate search tasks, assist in classic diagnostic classification tasks, and improve prognosis and theranostics. An essential step in enabling these advancements is to apply advances in machine learning and artificial intelligence from other fields to previously inaccessible pathology datasets, thereby enabling the application of new technologies to solve persistent diagnostic challenges in pathology. Here, we applied convolutional neural networks to differentiate between two forms of melanocytic lesions (Spitz and conventional). Classification accuracy at the patch level was 99.0%-2% when applied to WSI. Importantly, when the model was trained without careful image curation by a pathologist, the training took significantly longer and had lower overall performance. These results highlight the utility of augmented human intelligence in digital pathology applications, and the critical role pathologists will play in the evolution of computational pathology algorithms.

Squamous Cell Carcinoma in Perineal, Perianal, and Gluteal Hidradenitis Suppurativa: Experience in 12 Patients.

BACKGROUND: Few reports describe squamous cell carcinoma (SCC) arising in hidradenitis suppurativa (HS). OBJECTIVE: The 2 objectives were (1) to describe the clinical characteristics, pathologic findings, and postoperative outcomes of SCC in HS and (2) to assess whether human papillomavirus (HPV) is involved in the pathogenesis. MATERIALS AND METHODS: Cases of SCC in HS were identified through institutional medical records (1976-2013) and the Rochester Epidemiology Project. Tumor specimens were assessed for HPV DNA/RNA with in situ hybridization. RESULTS: Twelve patients were identified (11 Caucasians and 9 men). All SCCs involved gluteal, perianal, or perineal skin; 1 patient had, in addition, involvement of the vagina. Surgical excision was performed on all 12 patients, 4 of whom had a colostomy. Mean duration of HS before SCC development was 28.5 years (range, 15-53 years). Mean follow-up was 4.3 years after surgical excision. Seven of 12 patients followed had postoperative SCC recurrence. Squamous cell carcinoma caused death despite wide surgical excision in these 7 patients. Of the remaining 5 patients, 4 are unknown and 1 who did not recur had an in situ SCC (Bowen disease carcinoma). Squamous cell carcinoma was not associated with high-risk or low-risk HPV. CONCLUSION: Invasive SCC arising in HS carries a high risk of death.

Eosinophilic pustular folliculitis with underlying mantle cell lymphoma.

Eosinophilic pustular folliculitis (EPF) is a noninfectious condition characterized by folliculocentric papules, pustules, and plaques on the head, trunk, and extremities. Three subtypes of EPF have been described. Histopathology predominantly shows abundant eosinophils concentrated at the follicle, and treatment typically consists of topical corticosteroids or oral indomethacin. We present an unusual case of EPF in a 52-year-old man that preceded the diagnosis of mantle cell lymphoma.

Dermatofibrosarcoma Protuberans of Distal Extremities and Acral Sites: A Clinicopathologic Analysis of 27 Cases.

Dermatofibrosarcoma protuberans (DFSP) of the distal extremities and acral sites are extremely rare and incompletely characterized. Twenty-seven DFSP occurring in these sites were retrieved from our collective archives and reevaluated. Tumors occurred in 16 males and 11 females. Median age at presentation was 42.5 years (range, 7 to 78 y). Lesions involved the foot (18 with 6 in the toes and 2 on the plantar foot), distal ankle (4), hand (4 with 2 in the thumbs), and wrist (1). All cases showed predominantly classic DFSP morphology and were diffusely CD34 positive. Myxoid change, melanin pigmented, and giant cell fibroblastoma foci were each present in 1 case, respectively. Fibrosarcomatous change was present in 3 cases. Fluorescent in situ hybridization demonstrated PDGFB gene rearrangement in 9 of 10 tested cases. Clinical follow-up was available in 21 cases (median, 36.1 mo; range, 1 to 152 mo) and revealed 4 local recurrences. Four patients underwent digital amputation for unresectable recurrent disease. An additional patient underwent multiple resections with positive margins and elected to receive imatinib mesylate therapy. After a 2-year course, the patient has no evidence of residual disease (40 mo). No metastases were documented in any of the cases studied. The natural history of DFSP of distal extremities and acral sites is similar to that of its counterparts elsewhere. A high index of suspicion, careful morphologic examination for key histologic features of DFSP, and in selected cases, molecular studies to identify the pathognomonic COL1A1-PDGFB gene fusion should facilitate the distinction of these rare, locally aggressive neoplasms from morphologic mimics that may arise in distal extremities and acral sites.

Implementation of a Software Application for Presurgical Case History Review of Frozen Section Pathology Cases.

BACKGROUND: The frozen section pathology practice at Mayo Clinic in Rochester performs ~20,000 intraoperative consultations a year (~70-80/weekday). To prepare for intraoperative consultations, surgical pathology fellows and residents review the case history, previous pathology, and relevant imaging the day before surgery. Before the work described herein, review of pending surgical pathology cases was a paper-based process requiring handwritten transcription from the electronic health record, a laborious and potentially error prone process. METHODS: To facilitate more efficient case review, a modular extension of an existing surgical listing software application (Surgical and Procedure Scheduling [SPS]) was developed. The module (SPS-pathology-specific module [PM]) added pathology-specific functionality including recording case notes, prefetching of radiology, pathology, and operative reports from the medical record, flagging infectious cases, and real-time tracking of cases in the operating room. After implementation, users were surveyed about its impact on the surgical pathology practice. RESULTS: There were 16 survey respondents (five staff pathologists and eleven residents or fellows). All trainees (11/11) responded that the application improved an aspect of surgical list review including abstraction from medical records (10/11), identification of possibly infectious cases (7/11), and speed of list preparation (10/11). The average reported time savings in list preparation was 1.4 h/day. Respondents indicated the application improved the speed (11/16), clarity (13/16), and accuracy (10/16) of morning report. During the workday, respondents reported the application improved real-time case review (14/16) and situational awareness of ongoing cases (13/16). CONCLUSIONS: A majority of respondents found the SPS-PM improved all preparatory and logistical aspects of the Mayo Clinic frozen section surgical pathology practice. In addition, use of the SPS-PM saved an average of 1.4 h/day for residents and fellows engaged in preparatory case review.

Iatrogenic thyrotoxicosis and the role of therapeutic plasma exchange.

Thyroid storm or severe thyrotoxicosis results from extreme thyroid hormone elevation. Therapy includes medical management to prevent hormone production, release, recycling, and peripheral conversion while stabilizing adrenergic tone. Thyroid dysfunction is the usual cause but it can be due to excessive thyroid hormone ingestion. Therapeutic plasma exchange (TPE) has been used to rapidly remove protein-bound thyroid hormone. American Society for Apheresis guidelines make a weak recommendation to perform TPE in selected patients in the treatment of thyrotoxicosis based on low quality evidence. We present a case of excessive thyroid replacement hormone ingestion treated by TPE. The patient presented with the clinical picture of thyroid storm, including cardiovascular compromise and massively elevated total and free T3 (525 ng/dL, nl 80-200 ng/dL and 28 pg/mL, nl 2.0-3.5 11 pg/mL), which failed medical therapy. A single, one plasma volume TPE was performed. Both total and free T3 demonstrated substantial declines immediately after TPE with the patient's mental status returning to near-normal. Thyroid hormone extraction efficiency and collection efficacy were calculated as 37.1% and 40.8%, respectively. Prior to discharge on day 6, the patient's compounding pharmacy indicated that a "bad batch" of bovine thyroid gland derived replacement hormone had been produced. TPE appears to be effective in removing protein bound thyroid hormone in extreme iatrogenic thyrotoxicosis.

Histopathologic review of granulomatous inflammation.

Granulomatous inflammation is a histologic pattern of tissue reaction which appears following cell injury. Granulomatous inflammation is caused by a variety of conditions including infection, autoimmune, toxic, allergic, drug, and neoplastic conditions. The tissue reaction pattern narrows the pathologic and clinical differential diagnosis and subsequent clinical management. Common reaction patterns include necrotizing granulomas, non necrotizing granulomas, suppurative granulomas, diffuse granulomatous inflammation, and foreign body giant cell reaction. Prototypical examples of necrotizing granulomas are seen with mycobacterial infections and non-necrotizing granulomas with sarcoidosis. However, broad differential diagnoses exist within each category. Using a pattern based algorithmic approach, identification of the etiology becomes apparent when taken with clinical context. The pulmonary system is one of the most commonly affected sites to encounter granulomatous inflammation. Infectious causes of granuloma are most prevalent with mycobacteria and dimorphic fungi leading the differential diagnoses. Unlike the lung, skin can be affected by several routes, including direct inoculation, endogenous sources, and hematogenous spread. This broad basis of involvement introduces a variety of infectious agents, which can present as necrotizing or non-necrotizing granulomatous inflammation. Non-infectious etiologies require a thorough clinicopathologic review to narrow the scope of the pathogenesis which include: foreign body reaction, autoimmune, neoplastic, and drug related etiologies. Granulomatous inflammation of the kidney, often referred to as granulomatous interstitial nephritis (GIN) is unlike organ systems such as the skin or lungs. The differential diagnosis of GIN is more frequently due to drugs and sarcoidosis as compared to infections (fungal and mycobacterial). Herein we discuss the pathogenesis and histologic patterns seen in a variety of organ systems and clinical conditions.

Validation of diagnostic accuracy with whole-slide imaging compared with glass slide review in dermatopathology.

BACKGROUND: Teledermatopathology has evolved from static images to whole slide imaging (WSI), which allows for remote viewing and manipulation of tissue sections. Previous studies of WSI in teledermatopathology predated College of American Pathologists (CAP) telepathology validation guidelines. OBJECTIVE: We conducted a comprehensive retrospective WSI validation study of routine dermatopathology cases, adhering to CAP guidelines. METHOD: In all, 181 consecutive cases arranged into 3 categories (inflammatory, melanocytic, nonmelanocytic proliferations) were reviewed by 3 board-certified dermatopathologists via traditional microscopy (TM) and WSI. Intraobserver (TM vs WSI), TM intraobserver and interobserver (TM vs TM), and WSI interobserver (WSI vs WSI) concordance was interpreted using a 3-tier system. RESULTS: TM versus WSI intraobserver concordance (86.9%; 95% confidence interval [CI] 83.7-89.6) did not differ from TM versus TM intraobserver concordance (90.3%; 95% CI 86.7-93.1) or interobserver concordance (WSI: 89.9%; 95% CI 87.0-92.2, and TM: 89.5%; 95% CI 86.5-91.9). Melanocytic proliferations had the lowest TM versus WSI intraobserver concordance (75.6%; 95% CI 68.5-81.5), whereas inflammatory lesions had the highest TM versus WSI intraobserver concordance (96.1%; 95% CI 91.8-98.3). Nonmelanocytic proliferations had an intraobserver concordance of 89.1% (95% CI 83.4-93.0). LIMITATIONS: Efficiency and other logistical WSI parameters were not evaluated. CONCLUSION: Intraobserver and interobserver diagnostic concordance between WSI and TM was equivalent. Therefore, WSI appears to be a reliable diagnostic modality for dermatopathology.