Patrick S. Rush

Expression of epithelial-mesenchymal transition regulators SNAI2 and TWIST1 in thyroid carcinomas

Epithelial–mesenchymal transition is an important mechanism of epithelial tumor progression, local invasion and metastasis. The E-cadherin (CDH1) repressor SLUG (SNAI2) and the basic helix–loop–helix transcription factor TWIST1 inhibit CDH1 expression in poorly differentiated malignancies as inducers of epithelial–mesenchymal transition. Epithelial–mesenchymal transition has been implicated in progression from well to poorly differentiated/anaplastic thyroid carcinoma but the expression of SNAI2 and TWIST1 proteins and their phenotypic association in human thyroid cancers has not been extensively studied. We examined the expression of SNAI2, TWIST1 and CDH1 by immunohistochemistry in a panel of well-differentiated and anaplastic thyroid cancers and by qRT-PCR in thyroid cell lines. Ten normal thyroids, 33 follicular adenomas, 56 papillary thyroid carcinomas including 28 follicular variants, 27 follicular carcinomas and 10 anaplastic thyroid carcinomas were assembled on a tissue microarray and immunostained for SNAI2, TWIST1 and CDH1. Most (8/10) anaplastic thyroid carcinomas demonstrated strong nuclear immunoreactivity for SNAI2 with associated absence of CDH1 in 6/8 cases (75%). TWIST1 was expressed in 5/10 anaplastic thyroid carcinomas with absence of CDH1 in 3/5 (60%) cases. These findings were confirmed in whole sections of all anaplastic thyroid carcinomas and in a separate validation set of 10 additional anaplastic thyroid carcinomas. All normal thyroids, follicular adenomas, papillary and follicular thyroid carcinomas were negative for SNAI2 and TWIST1 (P<0.0001) and all showed strong diffuse immunoreactivity for CDH1 (P=0.026). Expression of SNAI2, TWIST1 and CDH1 mRNA varied in a normal thyroid, papillary carcinoma and two anaplastic thyroid carcinoma cell lines tested, but the highest levels of CDH1 mRNA were detected in the normal thyroid cell line while the anaplastic thyroid carcinoma cell line demonstrated the highest levels of SNAI2 and TWIST1 mRNA. Our findings support the role of epithelial–mesenchymal transition in the development of anaplastic thyroid carcinoma.

Angiosarcoma outcomes and prognostic factors: a 25-year single institution experience.

Objective:Angiosarcoma is an aggressive malignancy with endothelial differentiation and notoriously poor prognosis despite aggressive therapy. Limited data are available to guide management decisions. To address this limitation, we present a large retrospective analysis of angiosarcoma patients treated at a single institution over a 25-year period. Methods:To identify factors that impact angiosarcoma outcomes, we reviewed demographic, tumor, and treatment characteristics of angiosarcoma patients evaluated at the University of Wisconsin Hospital between 1987 and 2012. Results:The cohort included 81 patients diagnosed at ages 19 to 90 years (median, 67 y). Fifty-five (68%) patients presented with localized disease, whereas 26 (32%) presented with metastases. The primary sites were visceral/deep soft tissue (42%), head and neck/cutaneous (37%), breast (16%), and limbs in the setting of Stewart-Treves (5%). The 5-year overall survival was 40% with a median of 16 months. By univariate analysis, significant adverse predictors of survival included metastases at presentation, visceral/deep soft tissue tumor location, tumor size>5 cm, tumor necrosis, and the absence of surgical excision. A trend toward prolonged survival was observed with radiation therapy and for chemotherapy in patients with metastases. Age, sex, and prior radiation showed no correlation with survival. Conclusions:Our large single institution series confirms the poor prognosis of angiosarcoma, supports a central role for surgical excision in management, and highlights the need for novel therapies particularly in patients who present with metastatic disease.

#InSituPathologists: how the #USCAP2015 meeting went viral on Twitter and founded the social media movement for the United States and Canadian Academy of Pathology

Professional medical conferences over the past five years have seen an enormous increase in the use of Twitter in real-time, also known as “live-tweeting”. At the United States and Canadian Academy of Pathology (USCAP) 2015 annual meeting, 24 attendees (the authors) volunteered to participate in a live-tweet group, the #InSituPathologists. This group, along with other attendees, kept the world updated via Twitter about the happenings at the annual meeting. There were 6,524 #USCAP2015 tweets made by 662 individual Twitter users; these generated 5,869,323 unique impressions (potential tweet-views) over a 13-day time span encompassing the dates of the annual meeting. Herein we document the successful implementation of the first official USCAP annual meeting live-tweet group, including the pros/cons of live-tweeting and other experiences of the original #InSituPathologists group members. No prior peer-reviewed publications to our knowledge have described in depth the use of an organized group to “live-tweet” a pathology meeting. We believe our group to be the first of its kind in the field of pathology.

Expression of angiopoietin-TIE system components in angiosarcoma.

Angiosarcoma is an aggressive malignancy of endothelial differentiation. Potential roles of the endothelial angiopoietin-tunica interna endothelial cell kinase (ANGPT-TIE) system in angiosarcoma diagnosis, pathogenesis, prognosis and treatment are undefined. To examine the expression and prognostic significance of angiopoietin-1, angiopoietin-2, TIE1 and TEK (TIE2) proteins in angiosarcoma, we immunohistochemically evaluated clinically annotated human angiosarcoma samples. Correlations of protein expression with overall survival and pathological features were explored. The cohort included 51 patients diagnosed with angiosarcoma at the age of 30–86 years (median 67). The 5-year overall survival was 45% with a median of 26 months. Moderate to strong expression of angiopoietin-1, TIE1 and TEK (TIE2) was identified in the majority of angiosarcomas and moderate to strong expression of angiopoietin-2 was observed in 42% of angiosarcomas. Increased angiopoietin-1 expression correlated with improved survival. Non-significant trends toward longer survival were also observed with increased TIE1 and TEK (TIE2) expression. Increased expression of angiopoietin-2, TIE1 and TEK (TIE2) was associated with vasoformative architecture. No differences in expression of these proteins were observed when patients were segregated by age, gender, presence or absence of metastases at diagnosis, primary tumor location, radiation association or the presence of necrosis. We conclude that components of the ANGPT-TIE system are commonly expressed in angiosarcomas. Reduced expression of these proteins is associated with non-vasoformative and clinically more aggressive lesions.

Insulinoma-associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)

Merkel cell carcinoma (MCC) is a rare, clinically aggressive, cutaneous neuroendocrine (NE) neoplasm. As a tumor with small, round, blue cells, the histologic differential diagnosis for MCC can include melanoma, metastatic small cell carcinoma (SCC), nodular hematopoietic tumors, basal cell carcinoma (BCC), atypical variants of squamous carcinoma and the uncommon occurrence of primary cutaneous Ewing sarcoma. In cases with atypical histology or without the classic immunophenotype, the diagnosis can be challenging. Ultimately, immunohistochemistry (IHC) is essential to the definitive diagnosis of MCC and in difficult cases, the diagnosis may hinge entirely on the immunophenotype of the tumor cells. Insulinoma‐associated 1 (INSM1) is a transcription factor expressed in tissues undergoing terminal NE differentiation. As a nuclear protein tied to both differentiation and the cell cycle, INSM1 may offer additional utility in comparison to traditional, cytoplasmic markers of NE differentiation.

Idiopathic CD4 lymphocytopenia with giant cell arteritis and pulmonary mucormycosis.

Idiopathic CD4 lymphocytopenia (ICL) is characterized by a low CD4+ lymphocyte count in the absence of HIV or other underlying etiologies. We report a case of a 57-year old man with ICL and giant cell arteritis (GCA) who developed pulmonary mucormycosis, which, to our knowledge, is the first report of these occurring in a patient with ICL. Abnormally low total lymphocyte or CD4+ cell counts occurring in patients with autoimmune disorders should alert clinicians to the possibility of ICL. Immunosuppressive treatment should be used with caution in this context.

The wart on fire.

To the Editor , We read with great interest the July 2015 article by de Andrade et al. entitled, ‘Oral verruciform xanthoma: a clinicopathologic and immunohistochemical study of 20 cases’ and would like to propose a unique descriptor that vividly illustrates a histopathologic hallmark of these lesions. While not hooks for hanging hats, the catchy colorful sayings that are common in dermatopathology and dermatology add character to our descriptive practice and aid in the education of the newly initiated. Here, we suggest a picturesque phrase to describe a feature that we venture many have noticed but that attention has forgotten. We propose ‘wart on fire’ to describe the blazingly eosinophilic keratin characteristic of the verruciform xanthoma. Verruciform xanthoma is an uncommon papillary or ‘cauliflower-like’ solitary nodule or plaque typically occurring on oral mucosa or the scrotal, vulvar and perianal regions. Clinically, it may be difficult to differentiate from squamous papilloma, verruca vulgaris, condyloma acuminatum and verrucous leukoplakia. Histopathologically, they are chiefly described as having verrucous acanthosis with deep crypts and parakeratotic keratin displaying an orange–pink hue as well as numerous foamy lipid-laden macrophages (xanthoma cells) filling the papillary dermis.1 The rub here, however, is that these ‘numerous’ foamy macrophages may not always be so numerous and from low power may be indistinct.2 That being so, it is often the consistent low-power characteristic appearance of orangeophilic to blazingly eosinophilic keratin on a verrucous lesion giving this characteristic ‘wart on fire’ appearance that prompts us to look closer at the papillary dermis (Fig. 1). This descriptive phrase is catchy and calls attention to the key low-power histopathologic characteristics of the lesion being verruciform Fig. 1. Verruciform xanthoma (original magnification ×200, H&E). The low-power appearance of a verrucous lesion with blazingly eosinophilic keratin beckons our attention to the inconspicuous xanthoma cells within the papillary dermis. This biopsy material shows verrucous acanthosis of the epidermis, with a strikingly bright pink character of the superficial keratin. The papillary dermis is filled with expanded superficial vessels, aggregations of pale xanthoma cells and a superficial lymphocytic infiltrate.

Primary Cutaneous Adenosquamous Carcinoma of the Penis: The First Characterization of HPV Status in This Rare and Diagnostically Challenging Entity with Review of Glandular Carcinomas of the Penis

Glandular and pseudoglandular tumors of the penile skin are extremely uncommon and can present diagnostic challenges. Primary adenosquamous carcinoma of the penis is an extremely rare tumor, composed of distinct areas of malignant squamous and glandular cells, making it a diagnostically challenging entity. The World Health Organization (WHO) recognizes several subtypes of squamous cell carcinoma (SCC), each with its own distinctive pathologic appearance, clinical associations and prognosis. Among these variants is the exceedingly uncommon adenosquamous carcinoma (ASC), representing 1%–2% of all SCC of the penis. Recent large studies have interrogated the presence of human papillomavirus (HPV) in malignant penile tumors and have shown specific morphologic patterns and clinical presentations to associate with HPV status. However, given the rarity of the adenosquamous variant of SCC, it has largely been excluded from these studies. The glandular components of these lesions can present a confusing appearance, particularly when a large tumor is represented on a small biopsy. Here we describe a difficult histologic presentation of this rare tumor, with the first published characterization of the HPV status of this subtype. This case represents a distinctly unusual case of metastatic HPV‐positive primary cutaneous adenosquamous carcinoma of the penis.

Pathologic Features of Primary Pancreatic Malignancies

This chapter explores the pathologic features of benign and malignant lesions of the pancreas. As pathologic classifications evolve, particularly for cystic lesions and neuroendocrine tumors, it is important for physicians who treat patients with pancreatic neoplasms to fully evaluate these pathologic classifications.

Metastatic synovial sarcoma of the scalp: Case report

Synovial sarcoma is a malignant tumor of soft tissue that is rarely found in the head and neck. Even less common are metastasis within the head and neck.