Well-differentiated Neuroendocrine Carcinoma of the Larynx: Confusion of Terminology and Uncertainty of Early Studies.

Well-differentiated neuroendocrine carcinoma (also known as "carcinoid") of the larynx is an exceedingly rare tumor that has an epithelial origin. These tumors are malignant and have a low, but definite, risk of metastasis. Although it can be challenging, this tumor should be differentiated from moderately differentiated neuroendocrine carcinoma (also known as "atypical carcinoid"). The clinical and pathologic features of this tumor, as well as treatment and prognosis, are reviewed in detail.

Salivary myoepithelial cells: an addendum.

Salivary myoepithelial cells bear particular appendages and are involved in processes that have received incomplete attention in previous reviews. Here, cilia on myoepithelial cells are reviewed as regards substructure, occurrence, detection (electron microscopy, double immunofluorescence together with confocal microscopy), and roles (sensory reception, evolutionary homology, paracrine interaction). Attention is drawn to regressive changes affecting those cells (e.g. accumulation of lipofuscin), possible alterations of their cytoskeleton, internalization of apoptotic bodies and haemosiderin, and role in salivary microcalcification. The ability of differentiated salivary myoepithelial cells to divide is re-examined, particularly its increase in chronic inflammation and under experimental conditions. Caution with regard to histogenetic models of salivary neoplasia is re-emphasized; methodological deficiencies and areas of controversy are outlined; and lines of future research are suggested.

Polymorphous adenocarcinoma of the salivary glands: reappraisal and update.

Although relatively rare, polymorphous adenocarcinoma (PAC) is likely the second most common malignancy of the minor salivary glands (MiSG). The diagnosis is mainly based on an incisional biopsy. The optimal treatment comprises wide surgical excision, often with adjuvant radiotherapy. In general, PAC has a good prognosis. Previously, PAC was referred to as polymorphous low-grade adenocarcinoma (PLGA), but the new WHO classification of salivary gland tumours has also included under the PAC subheading, the so-called cribriform adenocarcinoma of minor salivary glands (CAMSG). This approach raised controversy, predominantly because of possible differences in clinical behaviour. For example, PLGA (PAC, classical variant) only rarely metastasizes, whereas CAMSG  often shows metastases to the neck lymph nodes. Given the controversy, this review reappraises the definition, epidemiology, clinical presentation, diagnostic work-up, genetics, treatment modalities, and prognosis of PAC of the salivary glands with a particular focus on contrasting differences with CAMSG.

Molecular markers in well-differentiated thyroid cancer.

PURPOSE: Thyroid nodules are of common occurrence in the general population. About a fourth of these nodules are indeterminate on aspiration cytology placing many a patient at risk of unwanted surgery. The purpose of this review is to discuss various molecular markers described to date and place their role in proper perspective. This review covers the fundamental role of the signaling pathways and genetic changes involved in thyroid carcinogenesis. The current literature on the prognostic significance of these markers is also described. METHODS: PubMed was used to search relevant articles. The key terms "thyroid nodules", "thyroid cancer papillary", "carcinoma papillary follicular", "carcinoma papillary", "adenocarcinoma follicular" were searched in MeSH, and "molecular markers", "molecular testing", mutation, BRAF, RAS, RET/PTC, PAX 8, miRNA, NIFTP in title and abstract fields. Multiple combinations were done and a group of experts in the subject from the International Head and Neck Scientific Group extracted the relevant articles and formulated the review. RESULTS: There has been considerable progress in the understanding of thyroid carcinogenesis and the emergence of numerous molecular markers in the recent years with potential to be used in the diagnostic algorithm of these nodules. However, their precise role in routine clinical practice continues to be a contentious issue. Majority of the studies in this context are retrospective and impact of these mutations is not independent of other prognostic factors making the interpretation difficult. CONCLUSION: The prevalence of these mutations in thyroid nodule is high and it is a continuously evolving field. Clinicians should stay informed as recommendation on the use of these markers is expected to evolve.

Applications of molecular testing in surgical pathology of the head and neck.

Molecular testing in routine surgical pathology is becoming an important component of the workup of many different types of tumors. In fact, in some organ systems, guidelines now suggest that the standard of care is to obtain specific molecular panels for tumor classification and/or therapeutic planning. In the head and neck, clinically applicable molecular tests are not as abundant as in other organ systems. Most current head and neck biomarkers are utilized for diagnosis rather than as companion diagnostic tests to predict therapeutic response. As the number of potential molecular biomarker assays increases and cost pressures escalate, the pathologist must be able to navigate the molecular testing pathways. This review explores scenarios in which molecular testing might be beneficial and cost-effective in head and neck pathology.

#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.

Differential Diagnosis in Neuroendocrine Neoplasms of the Larynx.

The differential diagnosis of neuroendocrine neoplasms of the larynx is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. These lesions have overlapping clinical and pathologic aspects and must be carefully considered in the differential diagnosis of laryngeal neoplasms. The prognosis and treatment are also different among these tumor types, which necessitates making these distinctions clinically. The current literature was reviewed to provide updated information regarding the epithelial-derived tumors, including carcinoid, atypical carcinoid, small cell neuroendocrine carcinomas, large cell neuroendocrine carcinoma, and squamous cell carcinoma with neuroendocrine component. These tumors are compared and contrasted with non-epithelial-derived tumors such as paraganglioma and nonmucosal tumors, such as medullary thyroid carcinoma. The morphologic and cytologic features are discussed, along with helpful immunohistochemical and ancillary investigations.

How phenotype guides management of non-conventional squamous cell carcinomas of the larynx?

Although the majority of laryngeal malignancies are the conventional squamous cell carcinomas (SCC), a wide variety of malignant epithelial tumors can affect the larynx. Current treatment guidelines are designed to guide clinicians in management of conventional laryngeal SCC. Less is known about the biological behavior and responsiveness to therapy and overall outcomes of other malignant epithelial lesions. Because a spectrum of disease biology is represented by these rare phenotypes, an understanding of the basic biology can help direct management to optimize clinical outcome in this group of patients. This review provides a critical analysis of literature relating to the diagnosis, management, and outcome of patients with non-conventional squamous malignant epithelial neoplasms of the larynx. Particular attention is paid to features which are at variance with the conventional SCC and how these impact on management of these rare tumors.

Frequent chromosomal aberrations and candidate genes in head and neck squamous cell carcinoma.

The knowledge of the biology of head and neck squamous cell carcinoma (HNSCC) has had relatively little impact on the improvement in oncologic outcome up to date. However, the identification of oncogenes and tumor suppressor genes (TSGs) involved in cancer progression contributes to the understanding of the molecular pathways involved in oncogenesis and could contribute to individual risk assessment and provide tools for improvement of treatment and targets for therapy based on the alterations in these pathways. The aim of this article is to review the chromosomal aberrations commonly found in HNSCC, to identify the genes in these chromosomal regions suggested to act as (candidate) oncogenes or TSGs, and to discuss the molecular mechanisms modulating their expression.

Incidental findings of thyroid tissue in cervical lymph nodes: old controversy not yet resolved?

The clinical significance of papillary or follicular thyroid tissue incidentally discovered in cervical lymph nodes during pathological assessment of neck dissections for non-thyroid cancers of the upper aero-digestive tract is critically reviewed. Special emphasis is given to controversies over normal-looking, nodal, thyroid follicles. Arguments for and against the benign nature of these follicles are considered together with processes that could be involved in their formation. The admittedly limited evidence suggests that benign, thyroid follicular inclusions rarely occur in cervical lymph nodes. Histological criteria that could be helpful in recognizing the inclusions, which include assessing their extent in conjunction with the size of the node, are discussed. Finally, an algorithm based on collaboration between specialists, correlating histological findings with imaging and loco-regional control of the upper aero-digestive tract cancer, is suggested for the management of patients with incidentally discovered, nodal thyroid tissue.

Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance.

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.

Lipomatous tumours of the head and neck: a spectrum of biological behaviour.

Lipomatous tumours are rare in the head and neck region. Their biological behaviour varies greatly, from absolutely benign to histologically benign but locally infiltrative and, finally, invasive with metastatic potential. Each lipomatous tumour has to be treated accordingly. It is of paramount importance before eventual surgery is planned to perform adequate imaging, diagnostic biopsy and careful assessment. Only in small (<5 cm), superficial soft tissue tumours or when magnetic resonance imaging has demonstrated specific features of lipoma, may diagnostic biopsy be omitted. In these cases, expectant management or simple excision is appropriate. Adequate preoperative diagnosis is important to assure adequate tumour control as well as optimal functional and cosmetic outcome. The major problem in the treatment of lipomatous tumours of the head and neck region is the presence of nearby delicate structures. Especially, wide surgical excision of liposarcomas may be hindered by anatomic constraints and may result in impaired functional and cosmetic outcome. Neoadjuvant radiotherapy and specific systemic chemotherapy may be helpful in the treatment of liposarcoma, especially when unresectable or when primary surgery is expected to result in poor oncological, functional or cosmetic outcome. Greater emphasis placed on the underlying biology of individual sarcoma subtypes, development and evaluation of novel therapies and greater specificity in the selection of chemotherapy agents based on activity in individual histological subtypes are expected to lead to improved efficacy of systemic treatment.

Salivary mucoepidermoid carcinoma revisited.

Clinicopathological features, prognosis and therapeutic strategies for mucoepidermoid carcinoma originating in salivary and salivary-type glands of the head and neck are reviewed. We emphasise histopathological aspects, appraise the value of histochemistry, electron microscopy, immunohistochemistry and cytophotometry, and discuss histogenesis and characteristic gene translocations. We additionally consider possible diagnostic difficulties, problems related to histological grading and accuracy of existing literature, and areas of controversy or uncertainty which may benefit from further investigations.

Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor.

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.

A perspective of comparative salivary and breast pathology. Part I: microstructural aspects, adaptations and cellular events.

This is the first part of a review comparing the pathology of salivary and mammary glands. Here, less obvious similarities and differences in functional histology and their influences on pathology are examined with emphasis on myoepithelial cells, stromal components, analogues of mucosa-associated lymphoid tissue, steroid receptors, and intraparenchymal cells of monocytic lineage. Particular cell phenotypes (oncocytic, apocrine, neuroendocrine and clear) are critically evaluated and responses to atrophy, infarction and fine-needle aspiration biopsy procedures are highlighted together with aspects of metaplasia, regeneration, ageing and microcalcification. Areas of controversy or uncertainty which may benefit from further investigations are also discussed.

Chondrosarcomas of the head and neck.

Chondrosarcoma represents approximately 11% of all primary malignant bone tumors. It is the second most common sarcoma arising in bone after osteosarcoma. Chondrosarcomas of the head and neck are rare and may involve the sinonasal tract, jaws, larynx or skull base. Depending on the anatomical location, the tumor can produce a variety of symptoms. Computed tomography and magnetic resonance imaging are the preferred imaging modalities. The histology of conventional chondrosarcoma is relatively straightforward; major challenges are the distinction between grade I chondrosarcomas and chondromas, and the differential diagnosis with chondroblastic osteosarcoma and chondroid chordoma. Surgery alone or followed by adjuvant radiotherapy is the treatment of choice. Radiotherapy alone has also been reported to be effective and can be considered if mutilating radical surgery is the only curative alternative. The 5-year survival for chondrosarcoma reaches 80%; distant metastases and/or local recurrences significantly worsen prognosis. The present review aims to summarize the current state of information about the biology, diagnosis and management of these rare tumors.

Causes of death of patients with laryngeal cancer.

Despite remarkable advances in the care of patients with laryngeal cancer over the past several decades, including a growing awareness of therapeutic complications and attention to quality of life, little is known about the causes of mortality in this population. In addition to the laryngeal malignancy itself, acute and late or chronic treatment-associated causes, second primary cancers, intercurrent disease and psychosocial factors are all responsible for patient morbidity and mortality. We examine the current literature related to the causes of death in patients with laryngeal cancer, in the hope of guiding future interventions to improve the longevity and quality of life of individuals with this cancer.

Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and potential diagnostic applications.

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that continues to be difficult to treat and cure. In many organ systems and tumor types, there have been significant advances in the understanding of the molecular basis for tumorigenesis, disease progression and genetic implications for therapeutics. Although tumorigenesis pathways and the molecular etiologies of HNSCC have been extensively studied, there are still very few diagnostic clinical applications used in practice today. This review discusses current clinically applicable molecular markers, including viral detection of Epstein-Barr virus and human papillomavirus, and molecular targets that are used in diagnosis and management of HNSCC. The common oncogenes EGFR, RAS, CCND1, BRAF, and PIK3CA and tumor suppressor genes p53, CDKN2A and NOTCH are discussed for their associations with HNSCC. Discussion of markers with potential future applications is also included, with a focus on molecular alterations associated with targeted therapy resistance.

Sinonasal tumors: a clinicopathologic update of selected tumors.

The sinonasal cavities show a wide variety of neoplasms of epithelial, mesenchymal, neural/neuroectodermal or hematopoietic origin. The differential diagnosis for these tumors may be difficult due to overlapping morphologies, variable patterns in ancillary studies, and potentially confusing terminology. In this report, an updated review of the spectrum of neoplasia is provided, using the World Health Organization 2005 classification as a guide. Classic tumors that are generally limited to the sinonasal tract are described and new information regarding molecular pathogenesis is reviewed. Also new entities that have the sinonasal tract as a site of predilection, such as sinonasal renal cell-like adenocarcinoma and NUT midline carcinoma are highlighted.

Assessing physician competency: an update on the joint commission requirement for ongoing and focused professional practice evaluation.

In 2008, the Joint Commission created 2 new hospital standards that revolve around competency assessment of credentialed and privileged healthcare practitioners. These are called Ongoing Professional Practice Evaluation (OPPE) and Focused Professional Practice Evaluation (FPPE). As many pathologists work as members of a hospital medical staff, either through primary employment or contract relationships, pathology departments and groups need to have OPPE and FPPE policies in place and should be using them to evaluate physicians for competency as part of a regular cycle. There are many subtleties in the standards, and careful attention to the details of the policies will be essential. Furthermore, as credentialing and privileging decisions may be made based upon the assessments that are carried out in OPPE and FPPE, it is quite important to follow internal policies consistently. This review describes OPPE and FPPE in detail, with an analysis of the Standards and the Elements of Performance. It also provides scenarios to illustrate the concepts and charts that can be used to create OPPE and FPPE documents for a practice.