Beyond entrepreneurship pdf files. IncidenceHead and neck cancers represent the sixth most common cancer worldwide with approximately 630,000 new patients diagnosed annually resulting in more than 350,000 deaths every year. More than 90% of head and neck cancers are squamous cell carcinomas (HNSCC) that arise from the mucosal surfaces of the oral cavity (OSCC, ICD-10 code: C00-08), oropharynx (OPSCC, ICD-10 code: C09-10 and C12-14) and larynx (ICD-10 code C32-9). While in Northern America and Europe, HNSCC accounts for 5-10% of all new cancer cases, there is wide geographical variation in the incidence and anatomic distribution of HNSCC worldwide. This variation is predominately attributed to demographic differences in the habits of tobacco use and alcohol consumption which contributes to the development of almost 80% of all HNSCC diagnosed globally. In high-risk countries (i.e.

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India, Sri Lanka, Bangladesh and Pakistan), OSCC is the most common cancer in men and the third most common cancer in women. Among the European countries, the highest incidence of OSCC is in France with high rates also noted in Hungary, Slovakia and Slovenia. In the United States (U.S.), HNSCC constitutes only the eighth most common cancer among men with approximately 53,600 patients diagnosed yearly and shows a considerably lower mortality with 11,500 patient deaths annually.

The decreasing incidence of OSCC and laryngeal SCC in the U.S. And in other developed countries coincides with decline in the use of tobacco products. By contrast, there is a recent upsurge in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) which is attributed to a change in the biologic driver of SCC in this region with an increasing frequency of an association with high-risk subtypes of human papilloma virus (HPV),. HPV associated SCC involves specific anatomic sites, specifically the oropharynx, which includes the base of the tongue (posterior 1/3 of tongue), tonsils, and the lateral surround pharyngeal walls (oropharynx) and coincides with Waldeyer’s ring of lymphoid tissue to include the nasopharynx. Conversely, HNSCC involving the anterior 2/3 of the tongue (oral tongue), floor of the mouth, palate, buccal mucosa, sulcus, and gingiva are considered HPV-unrelated sites.

Importantly, in the 1980s only 16% of carcinomas in the oropharynx in the U.S. Were HPV-positive whereas now 75% of OPSCC are HPV-positive. Indeed, HPV-driven HNSCC is responsible for a 25% increase in the incidence of HNSCC in the U.S. During this past decade, primarily among middle aged males.

Currently, the incidence of HPV-related HNSCC in the U.S. Is 6.2 per 100,000 and 1.4 per 100,000, for males and females, respectively. Currently, HPV-related OPSCC are recognized as a distinct subset of HNSCC because of its unique etiology, molecular pathogenesis, clinical presentation and therapeutic responses which will be discussed in detail later in this chapter. Tobacco, alcohol, panThe risk for developing HNSCC is associated with several factors including geographical location habits, diet, and genetic background. Among all etiologic factors, cigarette smoking and excessive consumption of alcohol represents the most important risk factors for the development of HNSCC and have a synergistic effect. Cigar and pipe smoking also increases the risk for developing OSCC, with pipe smokers having a predilection for lower lip SCC. Reverse smoking, a habit practiced in certain areas of India and South America, in which the lighted end of the cigarette is kept inside the mouth while smoking, causes HNSCC involving the hard palate.

Chewing of the “betel quid’ (also known as ‘pan’) is linked to the development of HNSCC of the buccal mucosa and the mandibular buccal sulcus. The habit of betel quid chewing is highly prevalent in countries with the highest incidence of OSCC (i.e. India, Pakistan, Bangladesh and Sri Lanka).

The betel quid consists of betel leaf, areca nut and slaked lime with or without added tobacco. Tobacco and areca nut are the two important carcinogens that are linked to the devolvement of OSCC.

The relative risk for OSCC was 7.74 for betel quid with tobacco whereas the relative risk reduces to 2.56 for betel quid without tobacco. The use of smokeless tobacco in the form of loose-leaf chewing tobacco, moist or dry snuff (finely ground tobacco) or chewing tobacco, a habit prevalent in the U.S. And Scandinavia (i.e. Sweden), is linked to OSCC with predilection in the mandibular buccal sulcus and gingiva. The relative risk for OSCC associated with chewing tobacco and moist snuff is quite low, ranging from 0.6 to 1.7, whereas the use of dry snuff is associated with a higher relative risk, ranging from 4 to 13. Although alcohol is not considered to be a carcinogen, excessive alcohol intake increases the risk of HNSCC most often acting synergistically with tobacco,.

Human papilloma virus (HPV)One fifth of HNSCC cases currently diagnosed in the U.S. Are not related to cigarette smoking and/or alcohol abuse. Infection with high-risk HPV types (HPV 16, 18. 31 and 33) play a causal role in the pathogenesis of OPSCC with distinct clinical and molecular features (.) Specifically, HPV High-risk type 16 accounts for 90% of HPV associated OPSCC in the U.S.

With rare accounts of HPV type 18, 33 and others reported in the literature. Interestingly, the shift in biology to HPV over tobacco associated SCC also accounts for the improvement in overall survival seen in HNSCC patients. HPV is a strong prognostic factor.

For SCC treated with similar therapeutic interventions (predominately radiation therapy with or without chemotherapy), HPV associated SCC showed an 82% three year survival compared to 57% survival for smokers with SCC. This survival difference continues at 5 years. However, when a patient has both an HPV+ tumor and a strong tobacco exposure, the prognosis of these patients may not parallel HPV+ tumors exclusively. To date how HPV and smoking status should be used to potential alter therapy remains debated and under investigation in clinical trials. Fanconi anemia and dyskeratosis congenitaFanconi anemia (FA; MIM 227650) and dyskeratosis congenita (DC; MIM 50, 224230) are two hereditary cancer syndromes that predispose to HNSCC at an early age. FA is a chromosomal instability disorder inherited as an autosomal- or X-chromosomal recessive trait due to germline mutations in one of 15 FA genes involved in the DNA repair pathway resulting in increased risks for bone marrow failure, leukemia and solid malignancies.

HNSCC is the most frequently diagnosed solid cancer in FA patients. The risk of HNSCC among FA patients is 800-fold higher than in the general population and occur at a younger age (median age: 27-years) than the general population,. Frequent oral screenings in FA patients for premalignant lesions is essential to try and reduce morbidity from OSCC. Similar to FA, DC is also an inherited bone marrow failure disorder that is caused by defects in telomere maintenance.

HNSCC is the most common solid malignancy seen in patients with DC. The oral cavity is the predominant site for HNSCC in both FA and DC patients, frequently occurring in the tongue. Hence, semiannual oral cancer screenings are recommended for both FA and DC patients beginning at a very young age.

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Age, Sex and Race predilection of HNSCCSimilar to other cancers, the risk of developing HNSCC also increases with age and the majority of HNSCCs occur in patients aged 50 years or over. The average age for smoking related HNSCC diagnosis is 60-years (median age: 63 years) whereas the average age for smokeless tobacco related HNSCC is 78-years.

HPV-related HNSCC is usually diagnosed at younger ages than tobacco related-HNSCC. The median age at diagnosis of HPV-related HNSCC is 58-years for men and 61-years for women. HNSCC is more common in men than in women and the ratios of OSCC and OPSCC by gender are currently about 1.5:1 and 2.8:1, respectively. In the U.S., African-American males have a higher incidence of conventional tobacco-related HNSCC than Caucasian males.

In contrast, HPV-related HNSCC are more frequently diagnosed in Caucasian males. TongueAnatomic sites of HNSCC exhibit significant geographic and demographic variation due to differences in their etiology. In the U.S., oral tongue is the most common intraoral site of HNSCC, with 7,100 new cases diagnosed annually, and accounts for 25-40% of all OSCC. The incidence of OSCC of the tongue has been steadily increasing from 1975 whereas the incidence of other OSCC sites has been decreasing.

Furthermore, recent studies report an increased incidence of oral tongue carcinomas arising in young white females who are more likely to be never smokers and never drinkers,. Oral tongue carcinomas occurring in young patients without the traditional risk factors of tobacco and/or alcohol abuse exhibit a more aggressive clinical course characterized by higher rates of loco-regional recurrences, shorter disease free intervals and poor survival and remain without a known etiologic cause,. Carcinomas of the oral tongue is the most aggressive of all OSCC and exhibit extremely high rates of occult lymph node metastases (not detected by clinical and radiographic imaging studies). Histopathologic guidelines used for the management of occult neck metastasis for early stage tongue SCC are described later.

Precursor lesions of HNSCCSimilar to other solid malignancies, HNSCC development is a multistep process often preceded by precursors which are commonly known as precancerous or premalignant lesions. The expert Working Group of WHO Collaborating Center for Oral Cancer and Precancer on the terminology, definitions and classification recently recommended the use of the term “potentially malignant disorders (PMD)” that includes premalignant lesions and conditions that have increased risk for malignant transformation. Premalignant conditionA generalized state of the oral cavity, which is associated with a substantially increased risk for HNSCC.Leukoplakia, erythroplakia and palatal lesions in reverse smokers are considered precancerous lesions, whereas actinic keratosis, oral submucous fibrosis and lichen planus are designated as precancerous conditions. Tobacco and alcohol-related HNSCC, are often preceded by lesions that present clinically as white (leukoplakia) or red (erythroplakia) patches or plaques. Currently, there are no known precursor lesions for HPV-associated oropharyngeal cancer. LeukoplakiaLeukoplakia is the most common and best-known form of PMD, accounting for 85% of all oral premalignant lesions. Leukoplakia is defined as a white patch or plaque that cannot be rubbed off and cannot be characterized clinically or histopathologically to any specific disease.

Hereditary, reactive, infectious and immune mediated disorders which present as intraoral white patches or plaques resembling leukoplakia are listed in. The risk of malignant transformation of leukoplakias varies markedly and is dependent on:.Etiology (smoking and/or alcohol use versus idiopathic).Clinical appearance.Location.Dysplasia grade on tissue biopsy. Autofluorescence visualization of tongue leukoplakias. (A) A 57-year old female with a history of cigarette smoking presented with a leukoplakia that is barely visible under white light. (B) Autofluorescence visualization revealed loss of fluorescence of this leukoplakia. Excisional biopsy of this leukoplakia revealed moderate epithelial dysplasia. (C) A 65-year old female with no history of tobacco use presented with a leukoplakia in her lateral surface of the tongue.

Extent of the leukoplakia involvement is markedly different when examined under white light (C) compared to autofluorescence visualization (D). Incisional biopsy of the lesion revealed moderate epithelial dysplasia (Inset).

In rare cases, patients may present with leukoplakia without any known etiological factors which is designated as idiopathic leukoplakia. Idiopathic leukoplakias have a significantly increased risk of malignant transformation than leukoplakias that are associated with specific etiologic factor (i.e.

Tobacco use).Leukoplakias most frequently occur at a single site (localized leukoplakia) and are more common in men and are associated with smoking. Localized leukoplakias presenting at a single site have two distinct clinical forms, namely homogenous and non-homogenous types, which are classified based on their surface color and appearance.

Homogenous leukoplakias are uniformly white flat (patch) or slightly raised (plaque) lesions and exhibit a low malignant transformation risk. Non-homogenous leukoplakias have a verrucous/granular surface, with or without red zones (speckled leukoplakia or erythroleukoplakia), and have a higher risk for malignant transformation than homogenous leukoplakias. The intraoral site of the leukoplakia is the most important factor in determining its malignant transformation risk. And other Western countries, leukoplakias in the floor of the mouth, soft palate and lateral/ventral surfaces of tongue have the highest risk for malignant transformation.

Overall, 9-37% of leukoplakias are expected to show either dysplasia, carcinoma in situ or invasive carcinoma at the time of biopsy. Proliferative verrucous leukoplakiaA multifocal, proliferative and progressive form of leukoplakia is recognized as proliferative verrucous leukoplakia (PVL). PVL commonly begins as a simple keratosis that eventually becomes verrucous and multifocal involving large contiguous sites. PVL is more common in elderly women, frequently involves the gingiva and is not associated with either smoking or alcohol abuse.

PVL tends to be persistent and frequently recurs even after surgical removal. PVL are high-risk lesions as almost 60-100% evolve into carcinoma over 10-20 years. Moreover, PVL generally lacks specific morphologic features including the classical microscopic features of epithelial dysplasia making PVL specifically a clinical diagnosis. Clinically and microscopically PVL may mimic the plaque variant of lichen planus because of its multifocal involvement and frequent presentation of lichenoid inflammation in the biopsy.

ErythroplakiaErythroplakia is a less common form of a precancerous lesion or carcinoma that presents as a well-defined red, raised velvety plaque that cannot be characterized clinically as any other disease. Oral mucosal conditions that may clinically resemble erythroplakia are listed in. Erythroplakias frequently occur in older adults in the floor of the mouth, ventral tongue and soft palate. Frequently, erythroplakias are associated with adjacent leukoplakias (erythroleukoplakia).

When biopsying these lesions it is important to take the biopsy from the erythroplakic areas. Erythroplakias, unlike leukoplakias, are high-risk premalignant lesions because almost all erythroplakias (100%) will exhibit microscopically either dysplasia or in situ/invasive squamous cell carcinoma at the time of biopsy. It should be emphasized that leukoplakia and erythroplakia are strictly clinical terms and are not associated with any specific histology and requires biopsy for definitive classification. Oral submucous fibrosisOral submucous fibrosis is considered a premalignant condition that is more prevalent among the South Asian population and its incidence is highest in the Indian subcontinent. Oral submucous fibrosis is a chronic, progressive condition characterized by diffuse mucosal rigidity due to dense fibrosis within the lamina propria that might extend into the underlying skeletal muscle.

It is caused by chewing betel quid containing areca nut. The extent and severity of this disorder is dependent on the amount of areca nut in the betel quid, duration and frequency of this habit. Oral submucous fibrosis frequently involves the buccal mucosa, tongue and soft palate. The affected mucosal surfaces appear pale, blanching marble-like with focal areas of atrophy and erythema. Patients commonly present with trismus, burning sensation and xerostomia; difficulties in speech, mastication and swallowing are experienced at the advanced stages. Oral submucous fibrosis is a premalignant condition with a malignant transformation rate of 8-12% over the period of 10-15 years.

Oral lichen planusLichen planus is the most common chronic autoimmune inflammatory disorder of oral mucosa that affects 1-2% of the adults in middle age. It is more common among females and tends to have multifocal lesions, often bilateral and symmetric in distribution.

It frequently involves buccal mucosa, gingiva and tongue. Ulcerative form of lichen planus involving the tongue of 57-year old female (A). Autofluorescence visualization demonstrates loss of fluorescence limited to the erythematous areas (arrows) due to inflammation (B).The malignant potential of oral lichen planus has been controversial in the past, however it is now considered to have a low malignant transformation rate of 1% over a 5 year period. Oral epithelial dysplasias (lichenoid dysplasia) may exhibit a chronic inflammatory cell infiltrate consisting of mostly lymphocytes that resembles the chronic inflammation seen in lichen planus, however has accompanying epithelial cellular alterations consistent with dysplasia as noted in,. Moreover, the plaque variant of lichen planus and PVL may also share similar clinical and microscopic features, leading to a misdiagnosis of lichen planus. Tissue Diagnosis.AutofluorescenceEpithelial hyperplasiaNo changeDysplasiaComplete or partial lossInvasive carcinomaComplete lossVerruciform hyperkeratosis (i.e.

PVL)No change or increaseInflammationComplete or partial lossIncreased vascularity or vascular tumorComplete or partial lossExtensive fibrosis (i.e. Submucous fibrosis)IncreasedExogenous pigmented lesion (i.e. Amalgam tattoo)Complete lossEndogenous pigmented lesion (i.e. Focal melanosis)Complete lossSurface bacterial or fungal colonization (i.e. Hairy tongue or Candidiasis)Altered red to orange fluorescence (porphyrin-related). Autofluorescence tissue imaging devices for screening of HNSCC and its precursorsEarly detection by screening and subsequent diagnosis of PMD is critical to prevent the onset of HNSCC, thereby decreasing morbidity and improving survival and quality of life. The current method for screening of HNSCC and its precursors is clinical oral examination (COE) which consists of visual inspection and palpation of oral mucosa under white light.

A number of studies have shown that COE has limited value in detecting and distinguishing benign oral mucosal lesions that mimic HNSCC and its precursors. Optical screening aids based on tissue reflectance and autofluorescence are increasingly used as adjuncts for COE for early detection of oral premalignancies. Detail descriptions of the light-based screening devices for PMD and their efficacy and limitations are reviewed elsewhere,.

Screening and diagnosis of PMDScreening: Evaluation of an asymptomatic patient for presence of PMDGold standard: Clinical oral examination by an expert clinicianAdjunctive screening aids:.Transepithelial brush biopsy (i.e. OralCDx Brush Test).Optical devices based on tissue reflectance visualization (i.e. ViziLite Plus & Microlux/DL).Optical devices based on tissue autofluorescence visualization (i.e. Oral epithelial dysplasiaPMDs need to undergo a scalpel biopsy for microscopic diagnosis that will dictate their malignant transformation risk and the appropriate therapeutic management.

Microscopically, these lesions may demonstrate epithelial hyperkeratosis, hyperplasia with or without dysplasia, carcinoma in situ or invasive SCC. As oral epithelial dysplasia is a microscopic diagnosis of precancer without a specific clinical appearance this term should not be used as a clinical description. Pathologically the term “epithelial atypia” is not synonymous with oral epithelial dysplasia and use should be restricted to epithelial changes not meeting the definition of dysplasia. An example of “epithelial atypia” is reactive and regenerative epithelial changes associated with inflammation adjacent to an ulcer. Hence, the use of the term “epithelial atypia” as a microscopic diagnosis for PMD may lead to confusion and should be avoided.

Both cytological and architectural alterations of the oral squamous epithelium are taken into account when grading oral epithelial dysplasia. However, microscopic evaluation of these features is subjective which leads to significant inter- and intra-observer variations in the diagnosis and grading of oral epithelial dysplasia. The malignant transformation rate of oral epithelial dysplasia varies considerably, ranging from 6% to 50% (mild dysplasia: 0-5%; moderate dysplasia: 3-15%; severe dysplasia: 7-50%). It should be noted a significant proportion of cases that were diagnosed as benign hyperkeratoses without dysplasia have progressed to cancer.

This may be attributed to underdiagnosing clinical PVL secondary to the lack of specific cytologic features associated with dysplasia.Although pathologic classification of oral epithelial dysplasia is not an optimal criterion for predicting the malignant transformation risk of PMD, histologic grading of oral epithelial dysplasia remains the gold standard to determine prognosis and to make treatment recommendation for these lesions. Currently, there are no reliable and reproducible molecular or genetic biomarkers that are superior to the diagnosis alone of oral epithelial dysplasia in predicting malignant transformation risks to carcinoma. Although, p53 mutations, loss of heterozygosity (LOH) and DNA ploidy analysis have been reported to predict the malignant transformation risk of PMD, neither of these techniques have been adopted in the clinical practice.

Loss of heterozygosity at chromosomes 3p and/or 9p increases the malignant transformation risk of oral epithelial dysplasias by 22.6 folds compared to dysplastic lesions with 3p and 9p retention. Oral epithelial dysplasias with additional loss of heterozygosity on chromosomes arms 4q and 17p reveal a 41.7-fold increased risk for malignant transformation. Currently, there is no general consensus regarding the management of oral epithelial dysplasia (OED) because of its variable biologic behavior and grading of dysplasia is not the best predictor of its malignant transformation risk. Moreover, inter- and intra-observer variability in grading of dysplasia is another confounding factor impacting treatment decisions.

The conventional management of OED is based on the dysplasia grade, clinical appearance and the location of the lesion. Strategies used in the management of dysplasia include careful follow-up, surgical resection, cryotherapy, laser treatment, photodynamic therapy- and non-surgical pharmacotherapy. Complete surgical excision is the most commonly practiced approach for treating clinically evident premalignant lesions with moderate to severe dysplasia,. Mild OED can be treated with either surgery or observation depending on the location and clinical appearance of the lesion.

Although surgical excision is the most effective method for preventing the recurrence and progression to invasive cancer, it is not always possible, especially in patients with OED that have widespread multifocal sites of involvement (i.e. Surgical excision of these lesions is associated with significant functional and cosmetic impairments. Patients with multifocal or widespread OED should be closely monitored and re-biopsied if there are significant changes in their clinical appearance. Laser ablation and cryotherapy are alternative methods for treating OED with widespread involvement. The major drawback of these treatments is that the tissue biopsy cannot be procured for histologic examination. If OED is going to be treated with laser ablation, multiple representative biopsies of the OED should be taken for histopathologic diagnosis before commencing ablation.

Cryosurgery with liquid nitrogen uses extreme cold to destroy dysplastic cells and is not widely used for treating OED because of higher incidence of malignant transformation in patients with OED treated with cryosurgery compared to patients treated with surgery alone. A new therapeutic approach for treating OED is photodynamic therapy which involves the topical or systemic administration of a photosensitizing agent (i.e. Aminolevulinic acid) that when activated by light causes cytotoxic-cell death by producing reactive oxygen species. Randomized controlled trials are required to determine the effectiveness of photodynamic therapy in treating OED. Several clinical trials have tested various therapeutic agents for treating OED and the relating data have been less impressive in preventing malignant transformation of OED. A recently published phase 1b study reported a 63% histologic response rate in OED when treated with a combination of erlotinib, an inhibitor of epithelial growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) inhibitor (Celecoxib). The data of this phase1b study appears promising but needs additional clinical studies before adopting this treatment strategy in routine clinical practice.

There is currently no evidenced based non-surgical pharmacotherapy for managing OED. Biopsy evaluationOften mucosal biopsies are superficial, curl/retract on removal, and may be tangential on sectioning.

On histologic review the determination of invasion may be limited or inconclusive secondary to scant underlying stroma and tissue orientation. Additionally, as a biopsy only accounts for one sampled area of the lesion, the pathologic interpretation must be correlated to the clinical findings for proper patient triage and a higher-grade process cannot be excluded within the lesion.

Thus a pathology reading of SCC at least in situ requires clinical correlation regarding the degree of suspicion for an invasive tumor and this pathologic reading may represent a limitation of any superficial biopsy sample. Communication with the pathologist and possible rebiopsy should be considered when the clinical impression is discordant with the pathologic reading.Rendering a diagnosis of SCC on a biopsy allows for further treatment planning however, the majority of prognostic factors rely on the evaluation of the resection specimen and the extent of disease. Specifically, pathologic factors in the primary tumor requiring evaluation include grade of differentiation or histologic subtypes, depth of invasion, perineural invasion, and margin status which all carry potential significance in determining the prognosis in HNSCC. Similarly, pathologic factors in regional metastasis including extracapsular spread impacts patient survival.

Histologic Subtypes of SCC‘Conventional/keratinizing’ SCC represents the vast majority (80%) of squamous carcinomas in the head and neck outside of the oro- and nasopharynx. Conventional SCC are graded based on both the extent of keratinization and cytologic maturation, as well as, the growth pattern, into well, moderately, and poorly differentiated.

This is the morphology most often associated with tobacco and/or alcohol related HNSCC.HPV associated SCC (HPV+ OPSCC) morphologically is often more monotonous with limited keratinization compared to conventional HNSCC. Terms including ‘nonkeratinizing’ and ‘basaloid’ have been confusingly used for HPV associated SCC. Since the use of these terms are not referring to the specific subtypes of SCC typically associated with these descriptors, non-keratinizing SCC of the nasopharynx and basaloid squamous cell carcinoma respectively; these terms should be avoided in this context.

Interestingly, the distinct morphologic feature of HPV+ OPSCC also applies to lymph node metastases from these tumors. The lymph node metastases are often largely cystic by imaging and on histology, leading to the false association with branchial cleft cysts/carcinomas. Cystic neck masses in an adult must be fully evaluated and metastatic SCC with cystic features is the leading diagnosis. Several less frequent subtypes of SCC are compared in and outlined below, each with their own challenges for diagnosis particularly on small biopsies. CA=carcinoma; F=females; LN=Lymph nodes; M=males; Mets=metastases; N/C=nuclear to cytoplasmic; WDSCC=well-differentiated SCCVerrucous carcinoma is a locally aggressive carcinoma showing a broad pushing growth downward and an exophytic/warty appearance.

Cytologically, the cells are bland with minimal alteration. Moderate dysplasia and thin angulated rete ridges should raise a concern for a hybrid or conventional SCC. This distinction is important, as pure forms of verrucous carcinomas do not metastasize, however hybrid verrucous carcinomas with conventional SCC require consideration for local and regional evaluation and treatment. Distinction on small biopsies may not be possible with the differential including verrucous hyperplasia, which only shows an exophytic component and is more localized. Complete excision of these lesions with normal adjacent mucosa allows for definitive classification and treatment of these lesions.

Histologic variants of squamous cell carcinoma. Histopathology prognosticators in SCCHistologic grading of SCC into well, moderate and poorly differentiated carcinomas is based on the degree of keratinization and cytologic maturation resembling background squamous mucosa.

Histologic grade of SCC remains of limited prognostic value though shows a trend for increased lymph node metastases in higher grade tumors. In comparison, perineural invasion, as well as, close margins (4 mm in an oral tongue SCC, the risk of occult metastasis has been reported as high as 40% and is considered a sufficient risk to warrant a prophylactic neck dissection in this cohort of patients moreover a recent study suggests 3 mm as a better break point in oral tongue SCC for prophylactic neck dissection,. Similarly a tumor thickness of 1.5 mm in the floor of mouth region portends a higher risk for occult nodal metastases favoring prophylactic neck dissection. Invasion of the tumor into muscle shows similar correlation with increased risk for regional metastases.

Other histologic factors including tumor invasive patterns and associated tumor inflammation may also allow for future risk-classification and is currently undergoing prospective validation. Study populationRiskAuthor/ConclusionStage I/II clinically N0Risk of Recurrence.Elective neck dissection.Observation (no neck dissection)1/28 pN0, 1/8 pN+11/35 (31%)Yuen et al. (71 patients)Elective neck dissection identified22% occult LN mets and reducedrisk of recurrenceClinically T1/T2 N0Tumor Depth of InvasionRisk of Occult MetastasesTongue 3.5 mm4/12 (33%)9/15 (60%)Favors neck dissection for floor ofmouth SCC 1.5 mm in thickness. MarginsAdequacy of margins must account for multiple anatomic and tumor parameters and is not simply black and white/positive or negative.

Studies evaluating treatment failure/local recurrence and margin status in OSCC have demonstrated even when a tumor is not at the margin being “close” increases risk for recurrence. The definition of “close margin” which would warrant consideration for additional tissue resection or adjuvant therapy remains variable however the best consensus is 5 mm from tumor for defining an adequate margin in HNSCC.

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Positive margins are considered SCC in situ or invasive tumor transected at the margin tissue edge. Additional considerations when studying distance to margins has been the marked shrinkage/retraction of tissue, particularly in tongue resections from the in situ distance measured by a surgeon from tumor to tissue margin versus the ex vivo pathology measurement.

Explanations for local failure with ‘close’ surgical margins include perineural invasion, lymphovascular invasion, and small tumor nests infiltrating beyond the tumor mass with intervening normal stroma. Moreover, molecular studies on histologically negative margins have shown a wide range of molecular alterations (LOH, p53, etc) including known alterations associated with malignant progression. The observation of precancerous molecular alterations also emphasizes the idea of field effect of precancerous changes in the oral cavity associated with tobacco exposure, which increases the risk for both local recurrence and the development of second primaries and may also contribute to local recurrence. Lymph node metastases and extracapsular extensionIn HNSCC, the most significant histologic prognostic factor for overall survival remains the presence of a positive lymph node metastasis followed by the presence of extracapsular extension (ECE) of tumor outside of a lymph node,. While the majority of the data is from oral SCC, the presence of ECE is now widely recognized as an adverse feature, including in other tumor types, which warrants consideration for intensified treatment regiments. Survival data has shown over a four- fold increase in distant metastases and in death rates compared to node negative patients. The most recent TNM tumor staging breaks extracapsular extension in lymph nodes into clinical/radiographic or macroscopic ECE versus pathologic microscopic ECE; this finding to date does not alter the overall staging of HNSCC patients.

TUMOR STAGINGUnified systems for tumor staging (TNM) have allowed for more consistent use within the oral cavity and lip, though overall staging of tumors arising in the oropharynx remains distinct. These sites begin with tumor size for T staging: Tis, is in situ; T1 are tumors up to 2 cm in greatest dimension; and T2 are 2 cm but 3 to 6, and 6 cm greatest dimension), number of lymph nodes (single versus multiple) and location (bilateral, contralateral) of the lymph nodes relative to the primary. The overall staging combining the pathologic T and N score differs in oral cavity versus oropharynx primaries with allowable lymph node positivity in stage II oropharynx. This system reflects the biological distinctions of SCC based on site of origin and the improved survival of OPSCC patients compared to OSCC patients. ImmunohistochemistryThe diagnosis of SCC is based on morphology and rarely requires ancillary studies for support of mucosal origin.

However, in small biopsies, particularly of high-grade tumors, confirmation of carcinoma and derivation as squamous origin is required. Immunohistochemistry utilizes antibodies specific to proteins (keratins in carcinoma, S100 and melanin in melanomas, CD45 in lymphomas, etc.) allowing for visualization of molecular expression under a light microscope. HNSCCs typically express squamous epithelial marker cytokeratins 5/6 and p63, a basal cell/stem cell-like marker, is also often diffusely positive. The work-up of high-grade basaloid tumors includes cytokeratin positivity (negative in lymphomas and melanomas), p63 (positivity in SCC, negative in solid adenoid cystic carcinomas), and neuroendocrine markers (synaptophysin, chromogranin), which would be negative in SCC and positive in neuroendocrine carcinomas, small cell carcinomas, and merkel cell carcinomas. Differentiating salivary tumors is performed primarily by their histologic pattern, however salivary tumor cells are positive for cytokeratin 7 and may show intracellular mucin (mucicarmine special stain). Makers for infectionsWhen evaluating tissue for infectious etiologies, special stains may be used to highlight the microorganisms.

Grocott’ s methenamine silver stain (GMS) is most widely used to highlight the wall of fungal organisms, with cultures advised for speciation. Periodic-Acid-Schiff (PAS) is frequently used to detect yeast and pseudo-hyphae (i.e. Candida) in tissue sections. While gram stain highlights gram positive and gram-negative bacteria, the high-level of background oral flora makes this test less useful in the oral cavity.

Actinomyces may form clusters visualized on morphologic review and are also highlighted by GMS and Gram stains, though hematoxylin and eosin (H&E) identification is sufficient to report the finding. HPV and p16Currently only HPV and p16 testing are routinely performed as prognostic biomarkers in HNSCCs, specifically only for the evaluation of SCCs arising in the oropharynx. Numerous methodologies exist for direct testing for HPV, however, in situ hybridization is the most universally used method allowing for screening of all known high risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) in one test on standard paraffin tissue sections,. Limited availability of this methodology for testing in the community, and concern for lower sensitivity compared to polymerase chain reaction (PCR) led to the evaluation of p16 as a surrogate marker for the presence of HPV in tumor cells. The tumor suppressor gene p16 is involved in cell cycle regulation that shows diffuse over-expression (cytoplasmic and nuclear) in tumor cells infected by HPV using standard immunohistochemical techniques. The mechanism of p16 over-expression is theorized to be secondary to viral components (E6 and E7) interfering with the function of Rb and p53 leading to compensatory up-regulation of p16.

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Early analysis of clinical trial tumor samples showed p16 expression in primary OPSCC tissue strongly correlated with HPV status and improved survival. While the association between p16 expression and HPV+ is strong in the oropharynx, p16 expression in other HNSCC tissue sites may be unrelated to HPV (as confirmed by negative PCR validation in multiple studies) stressing the need to perform a concurrent direct test for HPV confirmation if testing tissue outside of the oropharynx. Currently HPV tumor status is only used as a prognostic and etiologic factor, however on-going clinical trials are looking at treatment modifications for HPV+ tumors to reduce the long-term morbidities in this younger cancer population.

Additionally, while clinical trials specific to OPSCC prevention through HPV vaccination are infeasible, the implementation of the HPV vaccination in the population holds the potential for reducing the overall incidence of HPV. Vaccination is theorized to ultimately result in reducing HPV associated SCC in the head and neck in the coming decades as HPV in the oropharynx are the same high-risk types that cause cervical cancer and that the spread of HPV to the oropharynx has been linked to changes in sexual practices and increased sexual partners. Tp53 and EGFRMany HNSCCs overexpress the epidermal growth factor receptor (EGFR) a gene involved in cell proliferation, angiogenesis, migration, adhesion and invasion. This observation led to clinical trials and ultimately FDA approval of Cetuximab, a monoclonal antibody directed against EGFR, as an adjuvant treatment with radiation in HNSCC. However no biomarkers have been identified to date with regard to response or resistance to EGFR inhibitors in HNSCC.Mutation of the TP53 tumor suppressor gene is the most common and earliest genetic alteration associated with HNSCC. Missense mutations involving the DNA-binding domain of TP53 gene are seen in more than 50% of all conventional/tobacco-related HNSCC. Testing for TP53 mutation in biopsies of HNSCC and its precursors is labor intensive and not feasible in a clinical laboratory.

Moreover, currently there are no specific treatment guidelines for HNSCC with TP53 mutations. With the development of next generation sequencing and array technologies allowing for sequencing/screening of whole genes with minimal tumor tissue, new areas of research are on-going exploring p53 association with outcomes and therapies and may lead to new personalized care for HNSCC patients.

AbstractObjective To study the safety and efficacy of percutaneous fluoroscopic gastrostomy tube placement in patients with head and neck cancer.Design We conducted a retrospective case review of 92 consecutive cases. Comparable access procedures and relevant literature were reviewed.Setting Academic tertiary care center.Patients Patients with head and neck cancer who underwent percutaneous fluoroscopic gastrostomy tube placement between January 1996 and July 1996.Main Outcome Measures Immediate, delayed, and long-term complications; tube malfunction; and tube placement failure.Results The major complication rate was 1%; the minor complication rate was 8%; and the tube malfunction rate was 13%. The rate of successful tube placement was 98%.

None of the patients required hospitalization as a result of the procedure.Conclusions Percutaneous fluoroscopic gastrostomy tube placement is a safe, economical, and comfortable method that has distinct advantages over other gastrostomy tube placement methods. It is recommended for enteral feeding and nutritional supplementation in patients with head and neck cancer. PATIENTS WITH head and neck cancer are at particular risk for malnutrition before, during, and after their treatment as a result of a combination of local and systemic factors. Alcoholism, tobacco use, and poor diet are prevalent in this population and lead to decreased uptake of protein, vitamins, and minerals, resulting in malnutrition. Local tumor effects impair nutritional intake by causing dysphagia, odynophagia, distortion of taste and smell, and aspiration.

Systemic effects of cancer such as increased metabolic rate and accelerated protein catabolism lead to increased nutrient requirements. Surgery can cause anatomical alterations, pain, and dysmotility, and can predispose a patient to aspiration, further impairing a patient's ability to consume adequate calories. Radiation therapy and chemotherapy can cause mucositis, pain, edema, thickened secretions, and nausea, all of which can decrease a patient's appetite and motivation for intake. Severe constipation, a common adverse effect of narcotic analgesics, can further impair a patient's appetite. All of these factors can lead to severe weight loss, which potentially affects prognosis, quality of life, ability to heal, length of hospitalization, and cost of care.

For these reasons, patients with head and neck cancer require frequent nutritional assessment and intervention during all phases of treatment beginning at diagnosis. Education in proper nutrition and oral administration of high-calorie and -protein supplements are often not adequate to stabilize nutritional status. Therefore, intervention in the form of enteral or parenteral supplementation may be required. Enteral nutritional support is preferred over parenteral methods as it is easier to administer, is associated with a lower rate of sepsis, is more physiologic, and is more cost effective than parenteral methods.Current methods of obtaining enteral access include placement of a nasogastric tube, transcervical miniesophagostomy, open gastrostomy, laparoscopic gastrostomy, percutaneous endoscopic gastrostomy, and percutaneous fluoroscopic gastrostomy.

Nasogastric tubes are associated with a high incidence of reflux aspiration, nasal alar ulceration, acute rhinosinusitis, pharyngeal irritation, and patient discomfort. Esophagostomy tubes, while more comfortable for patients than the nasogastric tubes, are aesthetically displeasing to the patient and family. Surgically placed gastrostomy tubes are more comfortable and convenient than nasogastric or esophagostomy tubes but require general anesthesia for placement and are associated with a fairly high morbidity rate of 6% to 25%., Percutaneous endoscopic gastrostomy tube placement is a safe procedure that can be performed in the ambulatory care setting with the patient under intravenous and local sedation. Because general anesthesia is not needed, the procedure is less expensive and less risky than surgical gastrostomy, and recovery time is shorter. Complication rates for the endoscopic technique range from 4% to 20% in patients with head and neck cancer., Rates of tube placement failure in patients with head and neck cancer are high because of the location of their disease.

Esophageal stricture, supraglottic or glottic edema, and tumor mass can all interfere with tube placement by the endoscopic method. In 1 series, there was a 7% failure rate due to the tumor obstructing passage of the endoscope.

In addition, with the percutaneous endoscopic technique, the gastrostomy tube traverses tumor and oral flora before it is placed in the gastric wall, which can lead to tract infection and seeding of the abdominal wall with tumor.,Since 1992, The University of Texas M. Anderson Cancer Center, Houston, has been using fluoroscopically guided percutaneous gastrostomy tube placement to obtain enteral access in cancer patients. This placement method has proved to be efficient and safe: the rate of successful tube placement is 98% to 100%; the minor complication rate is 1% to 12%; and the major morbidity rate is 3% to 6%.The Section of Interventional Radiology at The University of Texas M. Anderson Cancer Center currently places an average of 40 gastrostomy tubes a month. There are no absolute contraindications to this procedure and it can be performed using local anesthesia alone. This review was conducted to determine the safety and efficacy of percutaneous fluoroscopic gastrostomy tube placement for patients with head and neck cancer who require enteral nutritional support.

TechniqueThe technique for tube placement was as follows: Oral intake was held beginning at midnight on the evening before the tube placement. Any available preexisting imaging studies of the abdomen were reviewed before the procedure. The patient was brought into the fluoroscopy suite, and intravenous sedation consisting of morphine and diazepam was administered as necessary. No antibiotics were administered. If the patient did not have a preexisting Dobhoff or nasogastric tube, a 5.0F to 6.5F Judkin catheter with a 0.035 Bentson guidewire (Cook Inc, Bloomington, Ind) was used for nasogastric intubation under fluoroscopic guidance. A contrast agent (diatrizoate sodium) was injected when necessary to traverse esophageal or pharyngeal obstruction.

Under fluoroscopic observation, the stomach was then insufflated with air, bringing the anterior gastric wall in apposition to the abdominal wall and displacing the colon and small bowel inferiorly. After preparation of the skin overlying the stomach and infiltration of subcutaneous tissues with 10 to 15 mL of 1% lidocaine, the stomach was punctured in the area of the horizontal portion of the greater curvature with a 7-cm, 18-gauge needle (Cook Inc) using a subcostal approach and fluoroscopic guidance.

Reduction of gastric wall tenting and aspiration of air suggested intragastric location of the needle tip. A 0.038-in Bentson guidewire (Cook Inc) was then passed through the needle, and the needle was withdrawn.

Conformation of the wire to the gastric outline confirmed the guidewire's intragastric location. A 12F to 14F peel-away dilator (Cook Inc) was then introduced over the wire and the tract was dilated.

Finally, a 12F Cope self-retaining loop catheter (Cook Inc) was placed into the stomach, and its position was confirmed by injecting a small amount of contrast agent through the catheter. The Cope loop-locking suture was tied. Gastropexy was not performed in any cases.

The nasogastric tube was removed at completion of the procedure. No skin retaining device was used. In some patients the tube was marked circumferentially 2.5 cm from the skin entry site to monitor tube migration. Povidine ointment and sterile dressing were applied to the site. ResultsThe most common tumor locations for patients needing percutaneous fluoroscopic tube placement were the oral cavity and oropharynx.Seventy-two patients (78%) had been treated with external beam radiotherapy within 6 months of the gastrostomy tube placement. Twenty patients (22%) had gastrostomy tube placement for other reasons, including extensive surgery, exchange for an existing tube, aspiration or dysphagia, and end-stage disease.There was one major complication of misplacement of the tube into the peritoneum. This resulted in intraperitoneal injection of contrast agent.

The patient eventually required exploratory laparoscopy and placement of an open surgical gastrostomy tube. This event accounted for the major complication rate of 1%. The rate of minor complications was 4%: 2 site infections were treated with antibiotics, and 2 instances of site bleeding were controlled with local pressure. No operative intervention was necessary for these procedure-related complications. There were no long-term complications. Other tube-related problems included migration of the tube into the duodenum, which caused cramping and diarrhea (9%) , tube dislodgment (13%), delayed leakage at the insertion site (4%), and inadvertent tube removal by the patient (2%). All malfunctions or dislodged tubes were successfully replaced or repositioned with an additional fluoroscopic procedure performed through the preexisting tube or tract.

Aspiration did not occur in any of the patients. There were no deaths associated with tube placement.

The rate of successful tube placement was 98%. CommentPercutaneous fluoroscopic gastrostomy tube placement has several advantages over the endoscopic technique for patients with head and neck cancer. With the fluoroscopic technique, a small-bore (5F to 6F) nasogastric tube is passed into the stomach for insufflation. Since this tube is much smaller than an endoscope, most obstructing lesions can be traversed using small amounts of injected water-soluble contrast agent and fluoroscopic guidance. The site infection rate is lower with this technique, presumably because the gastrostomy tube is not pulled through oral and pharyngeal flora.,Reported rates of site infection for the endoscopic technique range from 8.8% to 20%. In this study in which no antibiotics were administered before the procedure, the site infection rate was 2%.

With fluoroscopically guided tube placement, antibiotics are not necessary and are not routinely used. With this procedure, there is also a reduced chance for seeding of the tract with tumor as the gastrostomy catheter does not traverse the tumor. Furthermore, the radiologist can directly visualize the relevant anatomy during the procedure and can thus ensure accurate tube placement. Also, because passing a large-bore endoscope through the pharynx and esophagus is not necessary, placement in patients with bulky tumors is easier, deep sedation is obviated, and the risk of airway difficulties during the procedure is lower.

One of the patients in this study who underwent successful percutaneous fluoroscopic gastrostomy tube placement had a failed endoscopic placement secondary to a large pharyngeal tumor that obstructed the lumen and prevented passage of the endoscope. The complication rate of the fluoroscopic technique is comparable to the endoscopic technique and is well suited to the head and neck patient population.

The practice of marking gastrostomy tubes to keep track of intragastric length was recently introduced to prevent tube migration, the most frequent tube malfunction. The patients can monitor intragastric length at home, and adjust the catheter themselves if necessary.In conclusion, percutaneous fluoroscopic gastrostomy tube placement is a safe, effective, and appropriate way to provide enteral access for nutritional support of the patient with head and neck cancer.Accepted for publication July 8, 1998.Reprints: Jeffrey N. Myers, MD, PhD, Department of Head and Neck Surgery, M. Anderson Cancer Center, 5151 Holcombe Blvd, Houston, TX 77030.