Chi Chiung Grace Chen, MD

• Assistant Professor, Department of Gynecology and Obstetrics, Johns Hopkins
• Bayview Medical Center, Baltimore, Maryland

Lip cancer symptoms nausea cheap rocaltrol express, however treatment 1st metatarsal fracture purchase 0.25 mcg rocaltrol otc, shares many histopathological and prognostic features with oral cancer and will be considered in that category medications via g tube purchase discount rocaltrol. The defining criterion for a diagnosis of malignancy is invasion of epithelial cells through the basement membrane into the superficial lamina propria symptoms vitamin b12 deficiency cheap rocaltrol 0.25 mcg without prescription. Invasion may be seen as small breaches by a few cells or small islands medicine 2632 buy rocaltrol 0.25mcg line, to gross infiltration of the underlying connective tissues and submucosa by islands of malignant cells medicine 19th century buy rocaltrol 0.25 mcg online. This permeation of the tissues underlying the surface epithelium gives rise to the classical clinical signs of induration and fixation. All squamous cell carcinomas thus have an endophytic invasive component, where tumor islands can be identified deep to the surface epithelium. Many tumors may also rise above the surface of the mucosa, resulting in an exophytic component that is often associated with hyperkeratosis. This is variable but is most prominent in verrucous carcinoma-a variant characterized by a highly keratinized exophytic component. A well-differentiated squamous cell carcinoma shows a considerable amount of keratin production and within individual tumor islands there may be evidence of stratification with a quite well polarized basal cell layer. In some cases, well-differentiated tumors are clearly continuous with the overlying epithelium and show intact, large, branching rete pegs "pushing" into the underlying connective tissues. Conventional oral squamous cell carcinoma resembles, at least to some extent, the normal squamous epithelium from which it arises. Specific histological features that impact on prognosis will be discussed later in this chapter, but here the basic grading scheme is described. The epithelium shows maturation with prominent keratin formation and obvious basal layers. The most well-differentiated squamous cell carcinomas, with little atypia and a cohesive, pushing, invasive pattern, are typified by verrucous carcinoma (see below). Atypia in the form of nuclear and cellular pleomorphism and hyperchromatic nuclei are consistently seen and may be extensive. Poorly differentiated squamous cell carcinomas show little resemblance to a normal squamous epithelium, but it is important to note that it is still possible to recognize the tissue as being of epithelial origin. At the worst end of the spectrum, a lesion may be so poorly differentiated that it is not possible to infer its cell of origin on hematoxylin and eosin-stained sections alone. Overall, about 30% of oral cancers are well differentiated, 60% moderately and only 10% are poorly differentiated. The degree of differentiation may reflect the behavior of a lesion and is used, along with other more refined indictors, to predict the prognosis of individual lesions. Many workers have attempted to refine this classification, and grading schemes have evolved over the years. Verrucous carcinoma was first described by Ackerman in 1948 (40) as a distinctive variant of squamous cell carcinoma with characteristic clinicopathologic features. Predominantly a squamous mucosal lesion, verrucous carcinoma may also be found on cutaneous surfaces, especially in the anogenital region and lower extremities. Whether the carcinomas occur in the upper aerodigestive tract (verrucous carcinoma), on the genitalia (giant condyloma acuminatum) or on the extremities (carcinoma cuniculatum), they are similar. The mucous membranes of the head and neck are sites of predilection, with the oral cavity and larynx areas especially at risk. In its early stages, verrucous carcinoma may go unrecognized or be diagnosed as a benign mucosal or cutaneous verruciform growth. The carcinoma may be both persistent and progressive with a clinical phase that lasts several years. In some patients, however, the lesion appears suddenly or a period of slow growth is followed by rapid enlargement. The lesions are often, but not invariably, preceded by a clinical leukoplakia (43), which may be diffuse or focal, but is often part of the clinicopathological spectrum of proliferative verrucous leukoplakia (44,45). In the head and neck, lesions are most commonly encountered in the oral cavity or the larynx and in males between the ages of 50 and 80 years. In the oral cavity, the incidence among all forms of squamous cell carcinoma is between 2% and 4. The gross appearance of verrucous carcinoma is dependent on several factors: duration of the lesion, degree of keratinization and accompanying changes in the adjacent mucosa. The oral tumors often arise in clinical leukoplakia and are first relatively soft and circumscribed, becoming firmer and more irregular with time. When the carcinoma arises in the buccal mucosa or extends into the buccal sulcus, it can grow into the soft tissues overlying the mandible and become fixed to the periosteum. With continued growth, it can gradually destroy the periosteum and directly erode and destroy a considerable part of the mandible. The surface of the lesion is usually covered by a prominent keratin layer arranged in compressed invaginating folds. This clinical lesion is typical, with an exophytic verrucous or papillomatous surface. The lesion is exophytic with a papillary, verruciform surface, but also endophytic, with broad, bulbous rete pegs extending deep to the adjacent epithelium. This infiltrative margin is invariably a blunt "pushing" one usually with good circumscription. This seems to be a point of confusion for pathologists when invasion may be difficult to define. Intraneoplastic and stromal reactions to keratin or other cellular debris can be found. Because of the deceptively benign cytology of the neoplastic cells, an accurate surgical pathologic diagnosis requires a biopsy specimen that includes adjacent normal tissue and shows the invasive depth of the lesion. A fullthickness biopsy plus an appropriate clinical description of the lesion should permit a pathologist to distinguish a verrucous carcinoma from benign hyperplasia or other forms of squamous cell carcinoma. The presence of a regional lymphadenopathy does not help in differential diagnosis and may be misleading. Bona fide and unperturbed verrucous carcinomas do not metastasize, but can be associated with benign lymph node enlargements secondary to the inflammatory reaction associated with the carcinoma. Because they are low grade and often well demarcated, primary treatment for verrucous carcinoma, at any site, is preferably by surgical excision (42,47,48). However, primary radiotherapy has proved to be an effective treatment (49) and for large lesions or in cases where comorbidity limits treatment options chemotherapy with methotrexate has also proved effective (50). The phenomenon of "anaplastic transformation" following radiation therapy of a verrucous carcinoma has been a factor of contention in the treatment of the neoplasm and has probably been overestimated (42,49). The time interval, or latent period, between radiotherapy and the advent of a more biologically aggressive tumor is short. It is probable that lesions may progress to conventional squamous cell carcinoma as part of their normal natural history and conventional squamous cell carcinoma may be found within the lesion (42,43,51). The non-verrucous carcinoma element may be well-differentiated or range to poorly differentiated and non-keratinized. The true nature of this unusual carcinoma is uncertain and, although it is often regarded as a variant of verrucous carcinoma, it should probably be defined as a distinctive entity. In the oral cavity, it is most common on the maxillary or mandibular gingivae, but cases on the tongue and other sites have been reported (49,52). The majority of patients have been male with an average age in the sixth decade, but with a wide range from the second to the eighth decades. This has been described as an "inverse architectural epithelial proliferation" (54). The lesions show minimal cytological atypia, are always well differentiated but are associated with considerable local destruction and may permeate deep into muscle or underlying bone. Although primarily endophytic, the lesions are heavily keratinized and may present clinically with an exophytic papillary or verrucous surface resembling verrucous carcinoma. There may be clinical evidence of a large punctum or cavity where the lesion communicates with the surface mucosa. Carcinoma cuniculatum has been reported to have a good prognosis with few reports of metastases and an overall good survival. Because of the redefinition of these lesions, the clinicopathologic features of basaloid squamous cell carcinoma will need a reappraisal. However, in previous reports of lesions of the head and neck (62), they have been shown to occur in an elderly population with a mean age of 63 years and a male preponderance (82%). They have a predilection for the base of the tongue, pyriform sinus and supraglottic larynx and show an aggressive clinical behavior with a high incidence of metastases to cervical lymph nodes (64%) and distant spread (44%) to lungs, liver, bone, brain and skin. A more recent review of oral lesions found a similar age and gender distribution but noted that the tongue was the most common site followed by the floor of the mouth (59). Cords or trabeculae may also be seen, but prominent mitotic activity with many atypical or bizarre mitoses is typical. The squamous component is usually a conventional squamous cell carcinoma that is well to moderately differentiated and invasive. It is, however, the basaloid malignancy that sets this carcinoma apart as a distinctive variant of squamous cell carcinoma. The carcinoma may show both deep and lateral invasion at the time of diagnosis and a multifocal origin over a broad area of affected mucosa has been noted (64,65). The tumor forms folds of epithelium that permeate into the underlying tissues, forming crypt-like structures. Tumors arise from the overlying epithelium and there may be features of dysplasia and of conventional squamous carcinoma. However, this may depend on an adequate biopsy and careful examination of all the tissue for evidence of a surface origin and both elements. In small biopsies, only the basaloid component may be seen or the surface may be lost or obscured due to ulceration. These include salivary gland tumors, especially basal cell adenocarcinoma or solid adenoid cystic carcinoma, or other small cell carcinomas such as neuroendocrine carcinoma. Adenoid cystic carcinoma does not show foci of squamous cell carcinoma and there is also no dysplasia or carcinoma in situ in the overlying mucosa. Mitoses, nuclear pleomorphism and necrosis are also more conspicuous in basaloid squamous cell carcinoma. Basaloid squamous cell carcinoma is often associated with positive cervical lymph nodes at diagnosis, while adenoid cystic carcinoma is not. The immunoprofile is one of an epithelial malignancy (65,66), with positivity for broad-spectrum cytokeratins, but negative for neuroendocrine markers or S100 (66). Basaloid squamous cell carcinomas of the floor of the mouth, on the Squamous cell carcinoma / Spindle cell (sarcomatoid) carcinoma 179 other hand, have a higher recurrence rate and a worse prognosis than matched groups of conventional squamous cell carcinomas, regardless of the grade of the latter (67), and it is suggested that there is a correlation between the percentage of basaloid components and prognosis; carcinomas with more than 50% basaloid cells have a poorer prognosis (67). There is no evidence for a mixed epithelial and mesenchymal lesion and the term "carcinosarcoma" should no longer be used (71,72). About half of these cases arise in the tongue, either the mobile tongue or, in the case of oropharyngeal lesions, in the base of the tongue or lingual tonsils (78). The key diagnostic criteria for spindle cell carcinoma is the identification of a biphasic tumor with malignant spindle cells and a malignant epithelial component, which can be identified on microscopy or by immunocytochemistry. The epithelial malignancy may be conventional squamous cell carcinoma or may be dysplasia or carcinoma in situ of the overlying epithelium. Overall, up to 50% of cases may be composed entirely of spindle cells with no evidence of conventional carcinoma (73,74). However, if multiple sections are examined and carefully searched, evidence of squamous carcinoma or dysplastic epithelium can be found in over 80% of cases (75). It is most reliably found at the base or the margins of the spindle cell proliferation. In most cases, the carcinoma is demarcated and does not exhibit an intermingling with the spindle cell component. One pattern is often dominant in a given tumor, but most of the tumors manifest a combination. Cellular density and cytological atypia are variable, but most tumors are regarded as high grade or poorly differentiated (78). Multinucleated giant cells of either foreign body type or bizarre neoplastic forms are common (73,75). A very small number of lesions have been reported to show foci of metaplastic malignant mesenchymal elements in the form of osteosarcoma or chondrosarcoma (75,80). These are frequently associated with prior ionizing radiation to the site of the tumor. Immunocytochemistry for pan-cytokeratins can help identify small areas of squamous carcinoma or may identify an epithelial phenotype in the spindle cell component.

The difficulty of visualizing bone involvement may be further compounded by prior irradiation medications quotes 0.25 mcg rocaltrol with mastercard. In the great majority of non-irradiated mandibles symptoms ulcerative colitis buy on line rocaltrol, squamous cell carcinomas enter the medullary cavity through the upper borders of the mandible medications on nclex rn discount 0.25mcg rocaltrol mastercard, either through the occlusal ridge alone or in combination with a penetration of either the buccal or lingual plates (201 medicine vs nursing purchase rocaltrol online from canada,202) treatment diarrhea buy rocaltrol 0.25 mcg amex. This mode of invasion confirms the importance of cortical bone defects in the edentulous alveolus as a principal route for direct spread into the mandible medicine wheel colors cheap rocaltrol 0.25mcg visa. Size of the carcinoma does not appear to influence the incidence of bone involvement, but proximity of the tumor to bone does, and carcinomas involving the gingival margins appear to have a particularly high incidence of bone involvement. Having breached the cortex, the carcinoma can extend vertically and laterally and there may be a superficial extension beneath a relatively intact cortex and periosteum (201). Additional spread into the bone is accompanied by a rather consistent and prominent response among bone cells. Carter (201) divides the response into an osteoclastdependent phase and an osteoclast-independent phase of bone destruction. Each of these responses occurs in advance of the invading carcinoma and so it should be noted that malignant epithelial cells are rarely seen in actual contact with bone. The osteoclastic reaction is always greater than the osteoblastic response and is accentuated with rapidly growing, poorly differentiated carcinomas. Neither the osteoclastic nor osteoblastic responses are particularly affected by prior irradiation of the bone. New bone formation, mediated by osteoblasts, is most prominent in association with slowly advancing and indolent carcinomas. The presence of teeth significantly influences the pattern of bone invasion and involvement of the inferior alveolar nerve. McGregor and MacDonald (202,203) found a fourfold increase of neoplastic invasion of the inferior alveolar nerve in edentulous, mandibles as opposed to partially dentate, mandibles. In nearly every instance, however, nerve involvement was also associated with an extensive spread of the carcinoma in the medullary parts of the bone. Irradiation did not appear to affect the frequency or extent of nerve involvement. The difference in nerve-related spread between dentate and non-dentate mandibles was attributable to the difference in vertical height of the occlusal border above the mandibular canal. The progressive resorption of the alveolar surfaces seen in the edentulous mandible brings the alveolar nerve much closer to the mucosa and hence more vulnerable to a direct vertical spread of the carcinoma. The incomplete remodeling of cortical bone and multiple cortical defects associated with alveolar resorption allows direct continuity between the medullary cavity and the overlying mucoperiosteum (202). Furthermore, the bone changes associated with loss of teeth greatly reduces the distance a floor of mouth carcinoma needs to invade to reach the occlusal ridge. Spread of the carcinoma, either erosive or infiltrative, is nearly always through cancellous bone and its marrow spaces (203). Predicting invasion of the mandible is difficult, with computed tomography only showing a sensitivity of 52% and magnetic resonance imaging of 74% (204). In postirradiated cortical bone, it may not be possible to separate the periosteum, even in the absence of neoplastic invasion, and that can thwart the inspection of the cortex that is the key. It is likely that no single method will suffice in the determination of invasion of the mandible by oral squamous cell carcinomas. A combination of available techniques, tempered by clinical judgment, will produce the best result. Epithelial dysplasia of the oral mucosa-diagnostic problems and prognostic features. Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Is there a way for pathologists to decrease interobserver variability in the diagnosis of dysplasia Grading systems in head and neck dysplasia: their prognostic value, weaknesses and utility. Evaluation of a new binary system of grading oral epithelial dysplasia for prediction of malignant transformation. Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10-year period in South East England. Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from the Netherlands. Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral epithelial dysplasia: Clinical characteristics of western European residents. The prognostic value of individual grading parameters in small lingual squamous cell carcinomas. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. A methodologic study of histologic classification and grading of malignancy in oral squamous cell carcinoma. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Prediction of cervical lymph node metastases in squamous cell carcinoma of the tongue/floor of mouth. Optimal management of proliferative verrucous leukoplakia: a systematic review of the literature. Verrucous carcinoma of the oral cavity: a clinical and pathological study of 101 cases. Subset of patients with verrucous carcinoma of the oral cavity who benefit from treatment with methotrexate. Squamous cell carcinoma arising within verrucous carcinoma of the oral cavity: a case report. Pons Y, Kerrary S, Cox A, Guerre A, Bertolus C, Gruffaz F, Capron F, Goudot P, Ruhin-Poncet B. Clinicopathological evaluation of carcinoma cuniculatum: a variant of oral squamous cell carcinoma. Squamous cell carcinoma variants of the upper aerodigestive tract: a comprehensive review with a focus on genetic alterations. Human papillomavirus positive basaloid squamous cell carcinoma of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Basaloid squamous cell carcinoma of the head and neck: a clinicopathologic and flow cytometric study of 10 new cases with review of the English literature. Basaloid squamous cell carcinoma: an aggressive variant of squamous cell carcinoma of the head and neck region. Basaloid squamous cell carcinoma of the head and neck: a clinicopathologic and immunohistochemical study of 40 cases. Distinction of basaloid squamous cell carcinoma from adenoid cystic and small cell undifferentiated carcinoma by immunohistochemistry. Immunohistochemical p53 expression patterns in sarcomatoid carcinomas of the upper respiratory tract. Sarcomatoid carcinoma of the head and neck: molecular evidence for evolution and progression from conventional squamous cell carcinomas. Carcinosarcomas: current perspectives and an historical review of nosological concepts. Sarcomatoid (spindle cell) carcinoma of the head and neck mucosal region: a clinicopathologic review of 103 cases from a tertiary referral cancer centre. Spindle cell (sarcomatoid) carcinomas of the larynx: a clinicopathologic study of 187 cases. Spindle cell carcinoma of head and neck: an immunohistochemical and molecular approach to its pathogenesis. Spindle cell carcinoma of the upper aerodigestive tract: an analysis of 341 cases with comparison to conventional squamous cell carcinoma. The pathology of head and neck tumors: spindle cell lesions (sarcomatoid carcinomas, nodular fasciitis and fibrosarcoma) of the aerodigestive tracts. Expression of epithelial markers in sarcomatoid carcinoma: an immunohistochemical study. Myogenic differentiation in spindle cell (sarcomatoid) carcinomas of the upper aerodigestive tract. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunohistochemical study of 84 cases. Adenosquamous carcinoma of the head and neck: relationship to human papillomavirus and review of the literature. Oral adenoid squamous cell carcinoma: a report of three cases and review of the literature. Pseudovascular adenoid squamous-cell carcinoma of the oral cavity-a report of two cases. Pseudovascular adenoid squamous cell carcinoma of oral cavity: a mimicker of angiosarcoma. Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to humanpapillomavirus. Papillary squamous cell carcinoma of the head and neck: a clinicopathologic series. Clinicopathologic features of oral squamous papilloma and papillary squamous cell carcinoma: a study of 197 patients from eastern China. Papillary squamous cell carcinoma of the oral mucosa: a clinicopathologic and immunohistochemical study of 12 cases and literature review. Papillary squamous cell carcinoma of the oral mucosa: immunohistochemical comparison with other carcinomas of oral mucosal origin. Papillary squamous cell carcinomas of the upper aerodigestive tract: a clinicopathologic and molecular study. World Health Organization Classification of Tumours: Pathology and Genetics of Head and Neck Tumours 2005. Nonnasopharyngeal lymphoepitheliomas (undifferentiated carcinomas) of the upper aerodigestive tract. Undifferentiated carcinoma of the oropharynx: a human papilloma virus-associated tumor with a favorable prognosis. Squamous cell carcinoma of the oral cavity often overexpresses p16 but is rarely driven by human papillomavirus. Human papillomavirus testing in head and neck squamous cell carcinoma: best practice for diagnosis. Morphologic features of conventional squamous cell carcinoma of the oropharynx: "keratinizing" and "nonkeratinizing" histologic types as the basis for a consistent classification system. Recognition of nonkeratinizing morphology in oropharyngeal squamous cell carcinoma-a prospective cohort and interobserver variability study. Spindle cell carcinomas of the head and neck rarely harbor transcriptionally-active human papillomavirus. Human papillomavirus-associated oropharyngeal cancer: defining risk groups and clinical trials. Geograph ic variation in human papillomavirus-related oropharyngeal cancer: data from 4 multinational randomized trials. Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and potential diagnostic applications. Protocol for the Examination of Specimens from Patients with Carcinomas of the Lip and Oral Cavity. Head and neck cancers-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. Pitfalls and procedures in the histopathological diagnosis of oral and oropharyngeal squamous cell carcinoma and a review of the role of pathology in prognosis. Invasive front grading: reliability and usefulness in the management of oral squamous cell carcinoma. The prognostic implications of the surgical margin in oral squamous cell carcinoma. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue. Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of mouth. Depth of invasion as a predictive factor for cervical lymph node metastasis in tongue carcinoma. Micrometastases in carcinoma of the upper aerodigestive tract: detection, risk of metastasizing, and prognostic value of depth of invasion. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies. Cervical lymph node metastases in oral carcinoma related to the depth of invasion of the primary lesion.

Sequential loss of heterozygosity at microsatellite motifs in preinvasive and invasive head and neck squamous carcinoma 9 treatment issues specific to prisons purchase rocaltrol 0.25mcg with mastercard. Loss of heterozygosity at 11q23 in squamous cell carcinoma of the head and neck is associated with recurrent disease treatment xdr tb guidelines purchase rocaltrol 0.25mcg with amex. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers medicine expiration order genuine rocaltrol. Frequent allelic loss at chromosome arm 3p is distinct from genetic alterations of the Von-hippel lindau tumor suppressor gene in head and neck cancer medicine 6 times a day order discount rocaltrol. Predictive value of epigenetic alterations in head and neck squamous cell carcinoma treatment 3rd degree hemorrhoids purchase rocaltrol online. Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma symptoms 2016 flu buy rocaltrol 0.25 mcg low price. Disruption of transforming growth factor-beta signaling by five frequently methylated genes leads to head and neck squamous cell carcinoma pathogenesis. Detection of promoter hypermethylation in salivary rinses as a biomarker for head and neck squamous cell carcinoma surveillance. Identification of an epigenetic profile classifier that is associated with survival in head and neck cancer. Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer. Global hypomethylation identifies loci targeted for hypermethylation in head and neck cancer. Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing. A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. Genetic gains and losses in oral squamous cell carcinoma: impact on clinical management. Prognostic value of genomic alterations in head and neck squamous cell carcinoma detected by comparative genomic hybridisation. Identification of novel prognosticators of outcome in squamous cell carcinoma of the head and neck. Characterizing genetic transitions of copy number alterations and allelic imbalances in oral tongue carcinoma metastasis. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Differential gene expression signature between primary and metastatic head and neck squamous cell carcinoma. Identification of a predictive gene expression signature of cervical lymph node metastasis in oral squamous cell carcinoma. Oral tongue cancer gene expression profiling: identification of novel potential prognosticators by oligonucleotide microarray analysis. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers. A gene expression profile for nonsmoking and non-drinking patients with head and neck cancer. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Validation of a gene expression signature for assessment of lymph node metastasis in oral squamous cell carcinoma. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Involvement of potential pathways in malignant transformation from oral leukoplakia to oral squamous cell carcinoma revealed by proteomic analysis. Quantitative proteomic analysis of microdissected oral epithelium for cancer biomarker discovery. Proteomic analysis of human papillomavirus-related oral squamous cell carcinoma: identification of thioredoxin and epidermal-fatty acid binding protein as upregulated protein markers in microdissected tumor tissue. Proteomic analysis of oral cavity squamous cell carcinoma specimens identifies patient outcome-associated proteins. Prediction of recurrence-free survival using a protein expressionbased risk classifier for head and neck cancer. Differential proteomics identifies protein biomarkers that predict local relapse of head and neck squamous cell carcinomas. Transcriptome profiles of moderate dysplasia in oral mucosa associated with malignant conversion. Shah 9 Management of potentially malignant disorders of the mouth and oropharynx Rachel A. Shah 12 Radiotherapy Sean McBride 13 Chemotherapy Andres Lopez-Albaitero and Matthew G. Shah, and Bhuvanesh Singh 15 Reconstructive surgery: Soft tissue Adrian Sjarif and Evan Matros 16 Reconstructive surgery: Mandible Ivana Petrovic, Colleen McCarthy, and Jatin P. The clinician is expected to establish a preliminary diagnosis, develop a relationship of trust with the patient and family members, initiate additional diagnostic investigations, formulate a treatment plan and coordinate patient care with a multidisciplinary team. This article will address the anatomy of the oral cavity and oropharynx as well as the required components of initial in-office assessment of the patient and the key differential diagnoses to consider. Anatomical components such as fascial planes, neurovascular bundles and lymphatic drainage pathways directly impact on tumor spread, clinical presentation, treatment selection and prognosis. Understanding of the functional relationships of the oral cavity and oropharynx subsites, overlying skin, underlying bones (maxilla and mandible) and dentition, which play important roles in articulation, mastication, deglutition and facial expression as well as cosmesis, is central to achieving eventual best quality of life outcomes. The oropharynx is the posterior continuation of the oral cavity to the hypopharynx. Superiorly, the oropharynx extends to the lower border of the soft palate and inferiorly to the tip of the epiglottis. Apart from the lips, the mucosa is lined by non-keratinized, squamous epithelium and the submucosa is interspersed with minor salivary glands. Primary tumors of the oral cavity and oropharynx may arise from the surface epithelium, minor salivary glands or submucosal soft tissues, as well as from dental structures, bone or neurovascular tissues. They serve as a transitional zone between the skin of the face to the internal mucous membrane. The pre-vascular facial lymph nodes accompanying the facial artery and overlying the body of the mandible are at particular risk and are considered the first-echelon nodes for this primary site. Notably, the lack of bony or fascial planes leads to relatively fast and uninhibited tumor spread, particularly to the masticator space, making buccal mucosal cancer more aggressive with poorer prognosis (2,3). Laterally, the ridges form a gingivobuccal sulcus that transitions to the buccal and labial mucosa. The lower alveolar ridge transitions to the floor of the mouth medially, while the posterior margin borders the retromolar trigone and ascending ramus of the mandible. The medial margin of the upper alveolar ridge borders the hard palate, while the posterior margin is the maxillary tuberosity, which lies adjacent to the pterygopalatine arch. The tight adherence of thin mucosa to underlying bone leads to early bone invasion by malignant tumors arising at these sites. Deep extension in the marrow space involves the mandibular canal, causing anesthesia or paresthesia of the distal teeth and skin of the chin and potential for perineural spread of tumor to the skull base. Retromolar trigone the retromolar trigone is a small, triangular mucosal space bordered by the last lower molar tooth, the ascending mandibular ramus and the maxillary tuberosity. It connects with the buccal mucosa laterally and the anterior tonsillar pillar medially. Similar to the alveolar ridge, the mucosa is very thin and early bone invasion is common. These structures are supported by the underlying musculature (mylohyoid and hyoglossus muscles, as well as the genioglossus muscle). The four paired extrinsic muscles (genioglossus, hyoglossus, styloglossus and palatoglossus) are anchored to bone and adjust tongue position. The absence of fascial planes between these muscles enables tumors to easily penetrate and infiltrate among the various muscles. The base of the tongue has rich lymphatic drainage and, as a result, many patients will have early nodal involvement. In contrast to the oral tongue, there is often spread of disease across the midline. The tonsillar pillars are formed by mucosal folds over two small muscles; the palatoglossus muscle raises a fold of mucosa anterior to the tonsils, forming the anterior pillar at the lateral junction between the oral and oropharyngeal cavities. The posterior pillar is formed by raised mucosa from the superior fibers of the palatopharyngeus muscle. At the junction of the hard and soft palates are located the foramina through which the greater and lesser palatine nerves and vessels traverse. The incisive foramen, posterior to the maxillary incisors, conveys the nasopalatine vessels and nerve. Lesions spread easily through these foramina into the nasal vault or maxillary sinus. This mobile myomucosal fold fuses at the sides with the lateral wall of the pharynx and is essential for velopharyngeal competency and for opening of the estuation tubes. It is composed of an aponeurosis and five paired muscles that act upon it to alter its shape. These are the tensor veli palatini, levator veli palatini, palatoglossus, palatopharyngeus and muscle of the uvula (musculus uvulae). It is divided at the midline by the median fibrous raphe and is composed of paired intrinsic and extrinsic tongue musculature. Lymphatics drain from these structures into the retropharyngeal and upper deep cervical nodal basins. Tumors almost exclusively arise from the oropharyngeal surface of the soft palate. It consists of mucous membrane, submucosal layer, muscular layer and thin buccopharyngeal fascia. Immediately posterior to it lies the prevertebral fascia, separated by a potential space. The pharyngeal muscular wall is thin and consists of three curved, overlapping muscle sheets: the superior, middle and inferior constrictor muscles. Clinical assessment should include: Detailed description of all symptoms leading up to presentation Profile of the patient for risk factors for head and neck cancer Assessment of functional status and medical comorbidities Detailed physical examination, including adjunct instrumentation Obtaining of an in-office tissue sample where possible for histologic diagnosis referred otalgia, trismus, obstructive sleep apnea, snoring, a neck mass or weight loss. Superficial, early-stage tumors most often present as non-healing ulcers or exophytic growths, with varying degrees of pain and occasional episodes of bleeding from the lesion. These tumors are usually present for several weeks to a few months before most patients seek medical attention. Occasionally, a suspicious lesion may be identified by the dentist during routine dental examination in asymptomatic patients. Superficial ulcerations and early tumors are often assumed to be nonneoplastic lesions and are treated with oral rinses, topical therapy or antibiotics. In contrast to ulceration, some tumors present as exophytic growths that may be white to pink in color. Some white lesions present as papillary growths characteristic of a verrucous carcinoma. Halitosis secondary to a fungating necrotic tumor is present in some patients with massive lesions. Presentation can also be due to mass symptoms causing sleep apnea, snoring or a neck lump. Lip cancer usually presents as an ulcerative or proliferative lesion of the lower lip. This can be associated with numbness of the skin of the chin due to mental nerve involvement. Assessment of the length of lip involvement is important for surgical treatment planning. Very early lesions on the gum or the alveolar process can often be Additional investigations and referrals to members of the multidisciplinary head and neck team are discussed in Chapter 7. Clinical evaluation / History 243 mistaken for sepsis around a tooth socket and treated as gingivitis or dental infection. Lack of response to conservative treatment or the presence of a loose tooth, however, should immediately raise suspicion of a malignant process necessitating biopsy to establish tissue diagnosis. Similarly, changes to dentition or an ill-fitting denture should also raise suspicion in some patients with cancer of the gum or palate (5). The presence of an exophytic lesion associated with several contiguous loose teeth should raise the index of suspicion for a locally advanced malignant tumor of the gum. A history of a non-healing extraction site should also raise the suspicion of a neoplastic process in a patient who has undergone recent tooth extraction. Advanced lesions with invasion of the mandible and the inferior alveolar nerve may produce anesthesia of the skin of the chin. Oral consumption of food may be restricted to soft foods and patients may lose significant weight. Such adults presenting with nodal masses that are cystic clinically or radiologically can be mistaken as having branchial cleft cyst carcinomas. Progressive trismus is a manifestation of local progression of tumor in the masticator space and pterygomaxillary region, particularly from posterior extension of buccal mucosa or tonsilar tumors with invasion of the pterygoid muscles. However, trismus may also be related to chronic submucous fibrosis in patients with a habit of chewing areca (betel) nuts (6). Extension into the parapharyngeal space toward the base of skull can affect cranial nerve function.

Impact of perineural invasion as independent prognostic factor for local and regional failure in oral squamous cell carcinoma medications beginning with z order cheapest rocaltrol. Prognostic significance of perineural invasion in oral and oropharyngeal carcinoma treatment centers for depression cheap 0.25 mcg rocaltrol visa. Perineural invasion in oral squamous cell carcinoma: a discussion of significance and review of the literature treatment junctional rhythm buy rocaltrol visa. Perineural invasion in adenoid cystic carcinoma of the salivary glands: a valid prognostic indicator Epithelial nests in intraoral sensory nerve endings simulating perineural invasion in patients with oral carcinoma treatment 4 sore throat cheap rocaltrol 0.25 mcg mastercard. Prognostic value of vascular invasion in squamous cell carcinoma of the head and neck treatment jerawat di palembang discount 0.25 mcg rocaltrol free shipping. Significance of jugular vein invasion by metastatic carcinoma in radical neck dissection 4 medications at walmart buy rocaltrol overnight. Salivary gland duct involvement in oral epithelial dysplasia and squamous cell carcinoma. Detection of residual carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx: a study of surgical margins. The significance of "positive" margins in surgically resected epidermoid carcinomas. Prognostic and therapeutic value of frozen section determinations in the surgical treatment of squamous carcinoma of the head and neck. Refining the utility and role of frozen section in head and neck squamous cell carcinoma resection. Resection margin as a predictor of recurrence at the primary site for T1 and T2 oral cancers. The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Patterns and mechanisms of localized bone invasion by tumors: studies with squamous 202. Pre-surgical assessment of mandibular bone invasion from oral cancer: comparison between different imaging techniques and relevance of radiologist expertise. A comparison of different imaging modalities and direct inspection after periosteal stripping in predicting the invasion of the mandible by oral squamous cell carcinoma. Epithelial carcinogenesis is thought to be a multistep process involving the sequential activation of oncogenes and the inactivation of tumor suppressor genes in a clonal population of cells. These genetic and epigenetic changes generate concomitant phenotypic changes in the tumor cells that promote their survival and proliferation (1). Importantly, rather than merely providing a list of individual genetic alterations observed with some varying incidence/prevalence within small cohorts of patients, this chapter will instead focus on studies that have investigated entire classes of genetic changes at a global level. Where possible, it will also seek to correlate these molecular changes with potential improvements in the areas of diagnosis, prognosis and prediction. Currently, lesions are considered to be precancerous based on morphologic changes in individual epithelial cells and epithelial tissues. Similarly, mucosal lesions lacking histologic atypia at the time of biopsy may represent molecularly premalignant lesions. Therefore, histological findings can only be used to indicate that a particular lesion has an undetermined malignant potential and cannot be used for the prediction of malignant transformation. These findings also underscore that, at the present time, we are unable to accurately prognosticate on the basis of histologic changes and point to the need for protocols that address these diagnostic/prognostic challenges. Therefore, the development of molecularly based approaches to identifying predictive genetic changes prior to and after the development of cytologic atypia and/or tissue dysplasia would greatly improve the potential for early detection, prognostication and intervention. This is a common occurrence in cancer development and the repeated loss of a specific chromosomal region is often associated with the presence of a tumor suppressor gene. Some genes may contain one normal and one mutated allele-that is, be heterozygous-and still function normally. If this happens in a tumor suppressor gene, it predisposes the cell to turn malignant. Moreover, it also demonstrated that the inclusion of two additional markers, 4q/17p, improved the risk prediction. Using a three-tier prediction model, the authors were able to demonstrate 5-year progression rates of 4. First, as is often the case with three-tiered risk classifications, it is unclear how intermediate-risk patients would be managed. On the other hand, high-risk patients, with a 65% risk of progression over 5 years, would likely require aggressive treatment and monitoring (47,48). However, the management of patients characterized as intermediate risk is less clear. This risk is considerably different from both the low- and high-risk groups and these patients may benefit from a different and as-yet undefined preventive and surveillance strategy. If these low-risk lesions change their profiles with progression, one might be able to monitor lesions by way of sequential sampling. However, as with conventional histopathologic evaluation, the risk of sampling error will always be a confounder when incisional biopsies are performed. Further work is likely needed before one can develop monitoring and treatment protocols. While this was a small study requiring further validation, the implications of the findings are important as they raise the possibility of inaccurate diagnostic/prognostic tests as a result of sampling error. While there is some evidence suggesting variable diagnostic accuracy among techniques measuring ploidy in oral lesions (54), we will collectively consider all the methods for determining ploidy status. Aneuploidy is the situation in which a cell has an abnormal number of chromosomes instead of 46. A total of 1,313 patients and 1,477 biopsies with a diagnosis of dysplasia were initially included in the study. Of the lesions that progressed, 54% (7/13) of the lesions were aneuploid and 46% (6/13) were diploid. This retrospective analysis was performed on 273 patients and the results were correlated with histopathology and outcome. In total, 12% (32/273) of the patients underwent malignant transformation during the follow-up period, which ranged from 5 to 15 years. The authors found that both tests were able to provide prognostic information that was independent of the histopathological diagnosis. In addition, they found that the combination of tests allowed for the stratification of patients into three different risk groups for progression to cancer. Summary and clinical significance: Aneuploidy is observed in a large proportion of oral dysplastic lesions and there is some correlation between aneuploidy and histologic grade. In addition, the data indicate that aneuploid lesions may progress to cancer at a significantly faster rate than diploid lesions. However, cumulatively, the data have shown that the prognostic value for aneuploidy testing lacks sufficient diagnostic accuracy to reliably stratify patients into appropriate risk cohorts that could be used for monitoring and treatment. In normal tissues, unmethylated cytosine residues are found in high densities within CpG islands (areas with high concentrations of cytosine and guanine) that map close to the promoter region in approximately 40% of mammalian genes (68). However, there has been only one genome-wide study that has characterized the hypermethylation landscape of dysplastic oral lesions. For example, several cross-sectional studies have reported increased methylation of the p16 promoter region in dysplastic lesions (76,77). However, there were no differences in methylation patterns between the adjacent normal and dysplasia groups. These preliminary findings suggest that changes in CpG methylation patterns may be prominent in the later stages of progression. Summary and clinical significance: Hypermethylation of cancer-associated genes has been observed in dysplastic oral lesions with variable frequencies. The dysplastic lesions contained frequent copy number gains (>70%) in 3q, 5p, 6p, 7p, 8q and Xq. Conversely, frequent copy number losses (>70%) were identified for 1p, 2p, 3p, 5q, 9q, 12q, 17q and 22q. Drawing on data from a total of 12 studies, the authors observed that gains in 3q (36. Prior to this, additional large, multi-institutional, prospective studies are required. Several other frequent alterations have been observed in novel chromosomal regions of unknown biologic or clinical significance. Future studies of these chromosomal amplifications may identify key molecular changes and pathways critical for the progression of oral dysplasias and elucidate novel diagnostic and therapeutic strategies. These technologies allow for the comparison of entire transcriptomes between multiple samples of diseased and normal biospecimens. The development of these high-throughput platforms has garnered considerable interest from both basic science and clinical practice disciplines. A number of validated commercial biomarker gene sets are currently in clinical practice. In a systematic review, AbdulMajeed and Farah identified a total of 15 studies that performed expression profiling on dysplastic or potentially malignant lesions (120). Of those, they were able to obtain data for dysregulated gene sets from nine studies. They identified a total of 31 genes that had common expression changes in at least two independent studies. Whether altered expression of these genes has biologic significance or simply represents candidate surrogate biomarkers will require further investigation. The authors identified 346 differentially expressed genes, of which 132 demonstrated upregulation while 214 were downregulated. Summary and clinical significance: To date, there are limited data regarding the gene expression profiles of potentially malignant oral lesions. There are even fewer data regarding sequential changes in gene expression profiles when comparing paired samples of normal and diseased mucosa. However, the common gene list identified by AbdulMajeed and Farah and Zhang et al. They may be present as intergenic transcription units or found in the intronic sequences of protein-coding genes. The initial expression profiles were validated in an independent cohort of progressive and nonprogressive leukoplakias. Specifically, they observed upregulation of miR-708, miR-10b, miR-19a, miR-30e, miR-26a and miR660 and downregulation of miR-99, miR-15a, miR-197, miR-145 and miR-150. Unsupervised hierarchical clustering and principal component analysis identified 38 candidates that were associated with malignant transformation of oral leukoplakias. Further validation is still required to determine the diagnostic utility of this platform. This observation is particularly important when considering diagnostic markers and targeted therapies, as one would prefer to have a biomarker or target for therapy that was expressed across all stages of progression. In addition, they demonstrated that the combination of histopathologic evidence of dysplasia, in conjunction with increased miR-31 expression, improved prognostication for predicting which lesions were likely to undergo malignant transformation (136). In dysplastic tissue, 50% (164/325) of the transcripts demonstrated a twofold or greater differential expression compared to normal. The authors found differences in immune cell signatures at different stages of the histologic progression. Further investigation is required to better understand the specific mechanisms by which these nucleotides alter critical tumor phenotypes. As a result, we have a markedly improved understanding of the types and frequencies of genetic alterations observed in cancer (159,160). These include changes from single-nucleotide variations to large structural rearrangements. When combined with high-level bioinformatics analyses, the interrogation of these sizable and complex datasets has led to more refined understanding of cancer drivers and their roles in tumor biology. From a clinical perspective, it is hoped that this information will aid in the identification of novel biomarkers that can improve screening, diagnosis, prognosis and treatment. This apparent discrepancy is likely related to the extent of sequencing, depth of sequencing and bioinformatics. This is still largely true for the oral cavity (oral tongue, floor of the mouth, buccal mucosa and gingiva). There has been considerable interest in whether this group demonstrates a unique genomic profile that might provide implications for etiology as well as for identifying novel therapeutic opportunities. There has been considerable interest in identifying cancer-associated genes that have "druggable" potential (178). Similarly, analysis of whole-exome sequencing and reverse-phase protein array data by Lui et al.

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