Sandbox:ssw 2

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2], Sargun Singh Walia M.B.B.S.[3]

Oral Cancer

Oral cancer differential diagnosis The table below outlines the different types of tumors/cancers present in the oral cavity and oropharynx and how they can be differentiated from one another.

Type of cancer	Subtype	ICD-O Code	Epidemiology	Etiology	Localization	Clinical features	Diagnostic procedures
Squamous cell carcinoma Basaloid squamous cell carcinoma Papillary squamous cell carcinoma Spindle cell carcinoma Acantholytic squamous cell carcinoma Acantholytic squamous cell carcinoma Adenosquamous carcinoma	Verrucous carcinoma	8051/3	Older males 5th and 6th decades of life Males are affected more often than females	Tobacco smoking and alcohol Chronic smokeless tobacco HPV 16 and 18	Lip SCC arise almost exclusively on the lower lip Buccal mucosa Upper and lower gingiva Hard palate Anterior two-thirds of the tongue, including dorsal, ventral and lateral surfaces, and the floor of mouth	Often asymptomatic or may present with vague symptoms and mini- mal physical finding	Biopsy shows: Thickened club-shaped papillae and blunt stromal invaginations of well-differentiated squamous epitheli- um with marked keratinization
Lymphoepithelial carcinoma		8082/3	0.8-2% of all oral or oropharyngeal cancers	EBV	Tonsil and tongue(90%) Palate and buccal mucosa(others)	Intra-oral mass, which may be ulcerated. Some tumors can be bilateral	Biopsy chows: Syncytial sheets and clusters of carcinoma cells with vesicular nuclei Prominent nucleoli and ill-defined cell borders A rich lymphoplasmacytic infiltrate is present
Epithelial precursor lesions				Smoking	Seen in the entire digestive tract	White patches (leukoplakia) Red patches (erythroplasia/erythroplakia) Mixed red and white lesions	Biopsy shows: Hyperplasia Dysplasia, / squamous intraepithelial neoplasia / atypical hyperplasia Carcinoma in-situ
Proliferative verrucous leukoplakia and precancerous conditions			Average age at diagnosis is 62 years Women are more commonly afflicted (ratio, 4:1)	Unknown	Buccal mucosa in women Tongue in men.	An aggressive form of oral leukoplakia with considerable morbidity and strong predilection to malignant transformation	Biopsy shows: Extensive, thick, white plaques Hyperplasia and dense hyperkeratosis Verrucous surface with hyperkeratosis, hypergranulosis and a dense inflammatory infiltrate in the corium
Papillomas	Squamous cell papilloma and verruca vulgaris		Common in children and in adults in the 3rd to 5th decades Almost equal sex incidence with a slight male predominance	HPV subtype 2,4,6,7,10,40.	Any oral site may be affected mostly: Hard and soft palate Labial mucosa Tongue Gingiva	Soft, peduncu- lated lesions formed by a cluster of finger-like fronds or a sessile, dome- shaped lesion with a nodular, papillary or verrucous surface	Biopsy shows: Exophytic and comprise folds of hyperplastic stratified epithelium Cluster of finger-like projections
	Condyloma acuminatum		2nd and 5th decade with a peak in teenagers and young adults	HPV, most commonly types 6,11,16 and 18	Labial mucosa Tongue Palate	Painless, rounded, dome-shaped exophytic nodules 15mm in diameter Have a broad base and a nodular or mulberry-like surface that is slightly red, pink or of normal mucosal color. Lesions may be multiple and are then usually clustered	Biopsy shows: Several sessile, cauliflower-like swellings forming a cluster
	Focal epithelial hyperplasia		Disease of children,adolescents and young adults	HPV 13 and 32	All areas of the oral cavity Labial Buccal mucosa Tongue	Multiple asymptomatic lesions Soft rounded or flat plaque-like sessile swelling. Usually pink or white in color 2-10mm in diameter	Biopsy shows: Rounded sessile swelling formed by a sharply demarcated zone of epithelial acanthosis Koilocytes similar to those of squamous papilloma are usually present “Mitosoid bodies”, which are nuclei with coarse clumped heterochromatin resembling a mitotic figure
Granular cell tumour		9580/0	Arise in all age groups, with a peak between 40 and 60 years Females are affect- ed more often than males with an M/F ratio of 2:1	No etiological factors are known	Tongue is the most common single site Buccal mucosa Floor of oral cavity Palate Salivary gland	Lesion presents as a smooth, sessile mucosal swelling 1-2 cm in diameter with a firm texture. The overlying epithelium is of normal color or may be slightly pale	Biopsy shows: Plump eosinophilic cells with central small dark nuclei and abundant granular cytoplasm
Keratoacanthoma		8071/1	Occurs more often in whites Twice as frequent in men as in women	Associated with uptake of carcinogens(e.g. via particular smoking habits)	Skin of the face,including the lips Mucocutaneous linings may also be involved	Verrucous, speckled or ulcerated lesions Deep projections, which extend through minor salivary glands and underlying bone	Biopsy shows: Verrucous surface, keratinized clefts and penetrating squamous rete processes Minimal atypia seen
Papillary hyperplasia			Affects all age groups	Associated with: Wearing ill-fit- ting dentures Xerostomia Individuals with a high arched palate HIV infection	Palate	Asymptomatic nodular or papillary mucosal lesion	Biopsy shows: Parakeratinisation or less frequently orthokeratinisation
Median rhomboid glossitis				Associated with chronic candidal infection	Dorsum of the tongue at the junction of the anterior two thirds and posterior third	Forms a patch of papillary atrophy in the region of the embryological foramen caecum	Biopsy shows: Psoriasiform hyperplasia Areas of pseudoepitheliomatous hyperplasia Atypia may be present
Salivary gland tumours	Acinic cell carcinoma	8550/3	2-6.5% of all intraoral salivary gland tumors Age range was from 11-77 years, with a mean of 45 years Male to female ratio of 1.5:1	Unknown	Buccal mucosa Upper lip and Palate	Tumors usually form non-descript swellings	Biopsy shows: Solid sheets of epithelium with secretory material Ductal differentiation in tumors
	Mucoepidermoid carcinoma	8430/3	9.5-23% of all minor gland tumors	Unknown	Palate (most common site) Buccal mucosa Lips: upper>lower Floor of oral cavity Retromolar pad	Asymptomatic Bluish, domed swellings that resemble mucoceles or haemangiomas High-grade tumors result in ulceration, loosening of teeth, paraesthesia or anaesthesia	Low power microscopy shows low-grade tumor with both cystic and solid areas and an inflamed, fibrous stroma
	Adenoid cystic carcinoma	8200/3	42.5% of minor gland tumors	Unknown	Tongue Tonsil Oropharynx Cheek Lips Retromolar pad and gingiva	Slow growing submucosal masses and ulceration may be seen, particularly in the palate Pain, or evidence of nerve involvement, is usually only present in advanced tumors	Predominantly solid variant shows peri- and intraneural invasion.
	Epithelial-myoepithelial carcinoma	8562/3		Unknown
	Clear cell carcinoma, NOS	8310/3		Unknown
	Basal cell adenocarcinoma	8147/3	Rare in minor glands	Unknown	Palate Buccal mucosa Lip	Asymptomatic, smooth or lobulated sub-mucosal masses	Microscopically similar to basal cell adenocarcinomas of the major gland
	Cystadenocarcinoma	8450/3	32% developed in the minor glands	Unknown	Palate Lips Buccal mucosa Tongue and retromolar regions.	Slow growing and painless but some palatal tumors may erode the underlying bone causing sinonasal complex.
	Salivary duct carcinoma	8500/3	Rare in minor salivary glands Age range was 23-80 years (mean 56 years)	Unknown	Palate (65%) Buccal mucosa and vestibule (19%) Tongue (8%) Retromolar pad (4%) and upper lip (4%)	Tumours formed painless swellings but many in the palate can be painful and ulcerated or fungated with metastases to regional lymph nodes.	The range of microscopical appearances os similar to that seen in the major glands.
Salivary gland adenomas	Pleomorphic adenoma	8940/0	40-70% of minor gland tumors	Unknown	Palate Lips and Buccal mucosa	Painless, slow growing, submucosal masses, but when traumatized may bleed or ulcerate.	Biopsy shows cellular, and hyaline or plasmacytoid cell
	Myoepithelioma	8982/0	42% of minor gland tumors	Unknown	Palate of younger individuals
	Basal cell adenoma	8147/0	20% of minor gland tumors	Unknown	Upper lip Buccal mucosa		They are histologically similar to those in major glands.
	Cystadenoma	8149/0	7% of benign minor gland tumors	Uknown	Lips Cheek Palate
Kaposi sarcoma			Classic (elderly men of Mediterranean/EastEuropean descent) Endemic ( middle-aged adults and children in Equatorial Africa who are not HIV infected) Iatrogenic (Immunosuppressed, post-transplant) AIDS associated (HIV-1 infected individuals)	HHV-8 Immunologic, genetic, and environmental factors	Skin ( most common) Mucosal mem- branes such as oral mucosa, lymph nodes and visceral organs	Purplish, reddish blue or dark brown macules Plaques and nodules that may ulcerate	Biopsy of all 4 types show: Vascular slits and sparsely distributed lymphocytes.
Lymphangioma		9170/0	Pediatric lesions Present at birth or during the first years of life. Appear mostly in the head and neck area but may be found in any other part of the body	Developmental malformation Genetic abnormalities Turner's syndrome	Tongue	Circumscribed painless swelling Soft and fluctuant on palpation Irregular nodularity of the dorsum of the tongue	Biopsy shows: Thin-walled, dilated lymphatic vessels of different size, which are lined by a flattened endothelium
Ectomesenchymal chondromyxoid tumour of the anterior tongue			Age range varies from 9-78 years No distinct sex predilection.	Unknown		Asymptomatic, slow growing solitary nodule in the anterior dorsal tongue	Biopsy shows: Round, cup-shaped, fusiform, or polygonal cells with uniform small nuclei and moderate amounts of faintly basophilic cytoplasm Some tumors may show nuclear pleomorphism, hyperchromatism, and multinucleation
Focal oral mucinosis (FOM)			The lesion affects all ages Rare in children There is no distinct sex predilection.	Unknown	Gingiva( most common site) Palate Cheek mucosa and Tongue	Asymptomatic fibrous or cystic-like lesion	Histopathology is characterized by: Well-circumscribed area of myxomatous tissue Fusiform or stellate fibroblasts Absent or sparse reticular fibres Mucinous material shows alcianophilia at pH 2.5
Congenital granular cell epuli			Affects newborns Females are affected ten times more often than males	Etiology uncertain	Maxilla Mandible	Solitary, somewhat pedunculated fibroma-like lesion attached to the alveolar ridge near the midline	Ultrasound for prenatal diagnosis Immuno histochemically, the tumor cells are positive for vimentin and neuron specific enolase No reactivity with cytokeratin, CEA, desmin, hormone receptors or S-100
Haematolymphoid tumours	Non-Hodgkin lymphoma		Second most com- mon cancer of the oral cavity	There is no known etiology in most patients. Underlying immunodeficiency state (e.g. HIV Infection) Strong association with EBV	Palate, Tongue Floor of mouth Gingiva Buccal mucosa Lips Palatine tonsils Lingual tonsils or Oropharynx	NHL of the lip presents with: Ulcer Swelling, Discoloration Pain Paraesthesia Anaesthesia, or Loose teeth	Biopsy shows: Large cells with predominantly round nuclei and membrane-bound nucleoli, consistent with centroblastic morphology. Predominantly medium-sized cells with abundant pale cytoplasm. Large cells with round or multilobated nuclei
	Langerhans cell histiocytosis	9751/1		Associated with: Eosinophilic granulomas Multifocal multisystem disease	Jaw bone Intraoral soft tissues Gingiva Palate Floor of mouth Buccal mucosa and Tonsil	Common oral symptoms include: Swelling Pain Gingivitis Loose teeth and Ulceration	Biopsy shows ovoid Langerhans cells with deeply grooved nuclei, thin nuclear membranes and abundant eosinophilic cytoplasm
	Hodgkin lymphoma			Strongly associated with Epstein- Barr Virus	Waldeyer ring, particularly the pala-tine tonsil Oropharynx Alveolar crest of mandible Maxillary gingiva	Most patients present with localized disease (stage I/II), with Chronic tonsillitis or tonsillar enlargement with or without enlarged cervical lymph nodes
	Extramedullary myeloid sarcoma	9930/3		History of acute myeloid leukaemia, predominantly in the monocytic or myelomonocytic subtypes	Palate Gingiva	Isolated tumor-forming intraoral mass	Biopsy shows an Indian-file pattern of infiltration
	Follicular dendritic cell sarcoma / tumour	9758/3	Tumor of adulthood Affects wide age range	History of underlying hya-line-vascular Castleman disease	Tonsil Palate or Oropharynx.	The patients usually present with a painless mass	Biopsy usually exhibits borders and comprises: Fascicles Whorls Nodules, Storiform arrays or Diffuse sheets of spindly to ovoid tumour cells sprinkled with small lymphocytes
Mucosal malignant melanoma		8720/3	0.5% of oral malignancies Incidence 0.02 per 100,000	No known etiological factors associated with oral melanoma	80% arise: Palate Maxillary alveolus or gingivae Mandibular gingivae Others: Buccal mucosa Floor of mouth Tongue	Asymmetric with irregular outlines Macular pigmentation Nodular growth Ulceration Melanosis	Biopsy: S100 positive Negative for cytokeratins More specific markers include: HMB45, Melan-A or anti-tyrosinase

2017 ACG Guidelines for first-line treatment strategies of peptic ulcer disease for providers in North America

Strong recommendation

In patients with persistent H. pylori infection, every effort should be made to avoid antibiotics that have been previously taken by the patient.

The following regimens can be considered for use as salvage treatment: 1.Bismuth quadruple therapy for 14 days is a recommended salvage regimen. 2.Levofloxacin triple regimen for 14 days is a recommended salvage regimen.

Conditional recommendation

Bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options if a patient received a first-line treatment containing clarithromycin. Selection of best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics.

Clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options, if a patient received first-line bismuth quadruple therapy. Selection of best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics.

The following regimens can be considered for use as salvage treatment: 1.Concomitant therapy for 10–14 days is a suggested salvage regimen. 2.Clarithromycin triple therapy should be avoided as a salvage regimen. 3.Rifabutin triple regimen consisting of a PPI, amoxicillin, and rifabutin for 10 days is a suggested salvage regimen. 4.High-dose dual therapy consisting of a PPI and amoxicillin for 14 days is a suggested salvage regimen.

2017 ACG Guidelines for first-line treatment strategies of peptic ulcer disease for providers in North America

Strong recommendation

1.Bismuth quadruple therapy consisting of a PPI, bismuth, tetracycline, and a nitroimidazole for 10–14 days is a recommended fi rst-line treatment option. Bismuth quadruple therapy is particularly attractive in patients with any previous macrolide exposure or who are allergic to penicillin

2.Concomitant therapy consisting of a PPI, clarithromycin, amoxicillin and a nitroimidazole for 10–14 days is a recommended first-line treatment option

Conditional recommendation

1.Patients should be asked about any previous antibiotic exposure(s) and this information should be taken into consideration when choosing an H. pylori treatment regimen .

2.Clarithromycin triple therapy consisting of a PPI, clarithromycin, and amoxicillin or metronidazole for 14 days remains a recommended treatment in regions where H. pylori clarithromycin resistance is known to be <15% and in patients with no previous history of macrolide exposure for any reason.

3.Sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, clarithromycin, and a nitroimidazole for 5–7 days is a suggested first line treatment option.

4.Hybrid therapy consisting of a PPI and amoxicillin for 7 days followed by a PPI, amoxicillin, clarithromycin and a nitroimidazole for 7 days is a suggested first-line treatment option.

5.Levofloxacin triple therapy consisting of a PPI, levofloxacin, and amoxicillin for 10–14 days is a suggested first-line treatment option.

6.Fluoroquinolone sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, fluoroquinolone, and nitroimidazole for 5–7 days is a suggested first-line treatment option.

 Initial assessment and risk stratification 

Strong recommendation

1. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed.

Conditional recommendation

1.Blood transfusions should target hemoglobin  ≥ 7   g / dl, with higher hemoglobins targeted in patients with clinical evidence of intravascular volume depletion or comorbidities, such as coronary artery disease. 2. Risk assessment should be performed to stratify patients into higher and lower risk categories and may assist in initial decisions such as the timing of endoscopy, time of discharge, and level of care.  3. Discharge from the emergency department without inpatient endoscopy may be considered in patients with urea nitrogen < 18.2   mg / dl; hemoglobin ≥  13.0   g / dl for men (12.0   g / dl for women), systolic blood pressure  ≥  110   mm   Hg; pulse   100 beats / min; and absence of melena, syncope, cardiac failure, and liver disease, as they have  <1 %  chance of requiring intervention.

Pre-endoscopic medical therapy

Conditional recommendation

1. Intravenous infusion of erythromycin (250 mg ~ 30 min before endoscopy) should be considered to improve diagnostic yield and decrease the need for repeat endoscopy. However, erythromycin has not consistently been shown to improve clinical outcomes

2. Pre-endoscopic intravenous PPI (e.g., 80 mg bolus followed by 8 mg / h infusion) may be considered to decrease the proportion of patients who have higher risk stigmata of hemorrhage at endoscopy and who receive endoscopic therapy. However, PPIs do not improve clinical outcomes such as further bleeding, surgery, or death

3. If endoscopy will be delayed or cannot be performed, intravenous PPI is recommended to reduce further bleeding.

Gastric lavage

Conditional recommendation

1. Nasogastric or orogastric lavage is not required in patients with UGIB for diagnosis, prognosis, visualization, or therapeutic effect

Timing of endoscopy

Conditional recommendation

Timing of endoscopy 1. Patients with UGIB should generally undergo endoscopy within 24 h of admission, following resuscitative efforts to optimize hemodynamic parameters and other medical problems.

2. In patients who are hemodynamically stable and without serious comorbidities endoscopy should be performed as soon as possible in a non-emergent setting to identify the substantial proportion of patients with low-risk endoscopic fi ndings who can be safely discharged.

3. In patients with higher risk clinical features (e.g., tachycardia, hypotension, bloody emesis or nasogastric aspirate in hospital) endoscopy within 12 h may be considered to potentially improve clinical outcomes.

Endoscopic diagnosis

Strong recommendation

1. Stigmata of recent hemorrhage should be recorded as they predict risk of further bleeding and guide management decisions. The stigmata, in descending risk of further bleeding, are active spurting, non-bleeding visible vessel, active oozing, adherent clot, fl at pigmented spot, and clean base .

Endoscopic therapy

Strong recommendation

1. Endoscopic therapy should be provided to patients with active spurting or oozing bleeding or a non-bleeding visible vessel.

2. Endoscopic therapy should not be provided to patients who have an ulcer with a clean base or a fl at pigmented spot .

3. Epinephrine therapy should not be used alone. If used, it should be combined with a second modality.

4. Thermal therapy with bipolar electrocoagulation or heater probe and injection of sclerosant (e.g., absolute alcohol) are recommended because they reduce further bleeding, need for surgery, and mortality.

Conditional recommendation

1. Endoscopic therapy may be considered for patients with an adherent clot resistant to vigorous irrigation. Benefi t may be greater in patients with clinical features potentially associated with a higher risk of rebleeding (e.g., older age, concurrent illness, inpatient at time bleeding began).

2. Clips are recommended because they appear to decrease further bleeding and need for surgery. However, comparisons of clips vs. other therapies yield variable results and currently used clips have not been well studied .

3. For the subset of patients with actively bleeding ulcers, thermal therapy or epinephrine plus a second modality may be preferred over clips or sclerosant alone to achieve initial hemostasis .

Medical therapy after endoscopy

Strong recommendation

1. After successful endoscopic hemostasis, intravenous PPI therapy with 80 mg bolus followed by 8 mg/h continuous infusion for 72 h should be given to patients who have an ulcer with active bleeding, a non-bleeding visible vessel, or an adherent clot.

2. Patients with ulcers that have fl at pigmented spots or clean bases can receive standard PPI therapy (e.g., oral PPI once daily).

Repeat endoscopy

Conditional recommendation

1. Routine second-look endoscopy, in which repeat endoscopy is performed 24 h after initial endoscopic hemostatic therapy, is not recommended.

2.If further bleeding occurs after a second endoscopic therapeutic session, surgery or interventional radiology with transcathether arterial embolization is generally employed

Hospitalization

Conditional recommendation

1.Patients with high-risk stigmata (active bleeding, visible vessels, clots) should generally be hospitalized for 3 days assuming no rebleeding and no other reason for hospitalization. They may be fed clear liquids soon after endoscopy.

Strong recommendation

1.Patients with clean-based ulcers may receive a regular diet and be discharged after endoscopy assuming they are hemodynamically stable, their hemoglobin is stable, they have no other medical problems, and they have a residence where they can be observed by a responsible adult.

Long-term prevention of recurrent bleeding ulcers

Strong recommendation

1.Patients with H. pylori -associated bleeding ulcers should receive H. pylori therapy. After documentation of eradication, maintenance antisecretory therapy is not needed unless the patient also requires NSAIDs or antithrombotics.

2. In patients with NSAID-associated bleeding ulcers, the need for NSAIDs should be carefully assessed and NSAIDs should not be resumed if possible. In patients who must resume NSAIDs, a COX-2 selective NSAID at the lowest effective dose plus daily PPI is recommended.

Conditional recommendation

1.In patients with low-dose aspirin-associated bleeding ulcers, the need for aspirin should be assessed. If given for secondary prevention (i.e., established cardiovascular disease) then aspirin should be resumed as soon as possible after bleeding ceases in most patients: ideally within 1 – 3 days and certainly within 7 days. Long-term daily PPI therapy should also be provided. If given for primary prevention (i.e., no established cardiovascular disease), anti-platelet therapy likely should not be resumed in most patients.

2. In patients with idiopathic (non- H. pylori , non-NSAID) ulcers, long-term antiulcer therapy (e.g., daily PPI) is recommended.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [5], Sargun Singh Walia M.B.B.S.[6]

2017 ACG Guidelines for first-line treatment strategies of peptic ulcer disease for providers in North America

Strong recommendation

In patients with persistent H. pylori infection, every effort should be made to avoid antibiotics that have been previously taken by the patient.

The following regimens can be considered for use as salvage treatment: 1.Bismuth quadruple therapy for 14 days is a recommended salvage regimen. 2.Levofloxacin triple regimen for 14 days is a recommended salvage regimen.

Conditional recommendation

Bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options if a patient received a first-line treatment containing clarithromycin. Selection of best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics.

Clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options, if a patient received first-line bismuth quadruple therapy. Selection of best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics.

The following regimens can be considered for use as salvage treatment: 1.Concomitant therapy for 10–14 days is a suggested salvage regimen. 2.Clarithromycin triple therapy should be avoided as a salvage regimen. 3.Rifabutin triple regimen consisting of a PPI, amoxicillin, and rifabutin for 10 days is a suggested salvage regimen. 4.High-dose dual therapy consisting of a PPI and amoxicillin for 14 days is a suggested salvage regimen.