**Oral Cancer** THE UNIVERSITY OF WESTERN AUSTRALIA **A/Prof Omar Kujan** **BDS DipOPath MSc MFDS RCPS PhD FRCPath FFOMP RCPA** **DENT4217** **Oral Path Module** # # **Oral Cancer** **DENT4217 Oral Path Module** ## **Learning outcomes** * Oral cancer * Aetiology and pathogenesis * Clinical features * Histopathologic features * Diagnosis # # **Learning outcomes** - Oral cancer - Aetiology and pathogenesis - Clinical features - Histopathologic features - Diagnosis **Oral Malignant Neoplasms** Common: OSCC Less common: – Salivary gland tumours – Malignant melanoma – Lymphoma – Neoplasms of bone and connective tissue – Some odontogenic tumours – Maxillary antral carcinoma – Metastatic neoplasms – Kaposi sarcoma # # **Oral Malignant Neoplasms** - **Common:** OSCC - **Less common:** - Salivary gland tumours - Malignant melanoma - Lymphoma - Neoplasms of bone and connective tissue - Some odontogenic tumours - Maxillary antral carcinoma - Metastatic neoplasms - Kaposi sarcoma 6 O. Kujan Oral cancer ranks 12th among all cancers in prevalence worldwide (Khalili, 2008) and when combined with pharyngeal cancer, it ranks 6th (Warnakulasuriya, 2009). International Agency for Research on Cancer Lip, oral cavity, adults World Health Organization Male Female India United States of America China Pakistan Germany Japan Brazil Bangladesh Russian Federation France (metropolitan) United Kingdom Indonesia Spain Italy Thailand Canada Ukraine Poland Australia Mexico 1000 500 0 500 1000 Estimated numbers (x100) 5-year prevalence Incidence GLOBOCAN 2012 (IARC) (6.6.2016) Fig. 1.4 The incidence and mortality of head and neck cancer estimated in 2012 of the highest 20 countries over the world Table 1.1 Estimated incidence of lip, oral cavity and oropharyngeal cancer worldwide (all ages, both sexes), data derived from GLOBOCAN 2012 | Population | Numbers | Crude rate | ASR (W) | Cumulative risk | |:-----------------------------|:----------|:-----------|:----------|:-----------------| | World | 300,373 | 4.3 | 4.0 | 0.45 | | More developed regions | 100,823 | 8.1 | 4.7 | 0.54 | | Less developed regions | 199,550 | 3.4 | 3.7 | 0.42 | | Very high human development | 92,338 | 8.0 | 4.8 | 0.54 | | High human development | 45,734 | 4.4 | 3.8 | 0.45 | | Medium human development | 121,240 | 3.4 | 3.3 | 0.38 | | Low human development | 40,954 | 3.1 | 5.2 | 0.59 | | WHO African region (AFRO) | 13,484 | 1.5 | 2.7 | 0.30 | | WHO Americas region (PAHO) | 49,200 | 5.2 | 4.1 | 0.48 | # # **Epidemiology and Statistics** # ## **Global Prevalence** Oral cancer ranks 12th among all cancers in prevalence worldwide (Khalili, 2008) and when combined with pharyngeal cancer, it ranks 6th (Warnakulasuriya, 2009). Fig. 1.4 The incidence and mortality of head and neck cancer estimated in 2012 of the highest 20 countries over the world | Country | Male (Incidence) | Female (Incidence) | | :--- | :--- | :--- | | India | 1000 | 500 | | United States of America | | | | China | | | | Pakistan | | | | Germany | | | | Japan | | | | Brazil | | | | Bangladesh | | | | Russian Federation | | | | France (metropolitan) | | | | United Kingdom | | | | Indonesia | | | | Spain | | | | Italy | | | | Thailand | | | | Canada | | | | Ukraine | | | | Poland | | | | Australia | | | | Mexico | | | *(Estimated numbers (x100), 5-year prevalence, Incidence)* *Source: GLOBOCAN 2012 (IARC) (6.6.2016)* # ## **Estimated Incidence Worldwide (2012)** Table 1.1 Estimated incidence of lip, oral cavity and oropharyngeal cancer worldwide (all ages, both sexes), data derived from GLOBOCAN 2012 | Population | Numbers | Crude rate | ASR (W) | Cumulative risk | |:---|:---|:---|:---|:---| | World | 300,373 | 4.3 | 4.0 | 0.45 | | More developed regions | 100,823 | 8.1 | 4.7 | 0.54 | | Less developed regions | 199,550 | 3.4 | 3.7 | 0.42 | | Very high human development | 92,338 | 8.0 | 4.8 | 0.54 | | High human development | 45,734 | 4.4 | 3.8 | 0.45 | | Medium human development | 121,240 | 3.4 | 3.3 | 0.38 | | Low human development | 40,954 | 3.1 | 5.2 | 0.59 | | WHO African region (AFRO) | 13,484 | 1.5 | 2.7 | 0.30 | | WHO Americas region (PAHO) | 49,200 | 5.2 | 4.1 | 0.48 | # Incidence **Incidence ASR** **Both sexes** **Cancer of the lip and oral cavity** * **5.1+** * **3.8-5.1** * **2.5-3.8** * **1.9-2.5** * **<1.9** **No Data** **Source: GLOBOCAN 2012 (IARC)** **THE UNIVERSITY OF WESTERN AUSTRALIA** **International Agency for Research on Cancer** **World Health Organization** # ## **Incidence by Region (GLOBOCAN 2012)** **Cancer of the lip and oral cavity (Both sexes)** **Incidence ASR (Age-Standardized Rate)** - **5.1+** - **3.8-5.1** - **2.5-3.8** - **1.9-2.5** - **<1.9** - **No Data** *Source: GLOBOCAN 2012 (IARC)* **Mortality** **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** **Mortality ASR** **Both sexes** **Cancer of the lip and oral cavity** * **2.2+** * **1.6-2.2** * **1.1-1.0** * **0.67-1.1** * **<0.07** * **No Data** **Source: GLOBOCAN 2012 (IARC)** **International Agency for Research on Cancer** **World Health** **Organization** # ## **Mortality by Region (GLOBOCAN 2012)** **Cancer of the lip and oral cavity (Both sexes)** **Mortality ASR (Age-Standardized Rate)** - **2.2+** - **1.6-2.2** - **1.1-1.0** - **0.67-1.1** - **<0.07** - **No Data** *Source: GLOBOCAN 2012 (IARC)* **Incidence Projection 2035** **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** **International Agency for Research on Cancer** **World** **Lip, oral cavity** **Number of new cancers in 2035 (all ages)** **Male** **Female** **167360** **327537** **0** **50000** **100000** **150000** **200000** **250000** **300000** **350000** **400000** **Incidence in 2012** **Demographic effect** **GLOBOCAN 2012 (IARC) (8.6.2016)** **GLOBOCAN 2012 (IARC) (8.6.2016)** # ## **Incidence Projection (2035)** **Lip, oral cavity - Number of new cancers in 2035 (all ages)** - **Male:** 327,537 - **Female:** 167,360 *Effects considered: Incidence in 2012, Demographic effect* *Source: GLOBOCAN 2012 (IARC) (8.6.2016)* Mortality Projection 2035 **International Agency for Research on Cancer** **World** **Lip, oral cavity** **Number of cancer deaths in 2035 (all ages)** THE UNIVERSITY OF WESTERN AUSTRALIA Male - Female - 0 20000 40000 60000 80000 100000 120000 140000 160000 180000 200000 Mortality in 2012 Demographic effect 162614 80272 GLOBOCAN 2012 (IARC) (8.6.2016) # ## **Mortality Projection (2035)** **Lip, oral cavity - Number of cancer deaths in 2035 (all ages)** - **Male:** 162,614 - **Female:** 80,272 *Effects considered: Mortality in 2012, Demographic effect* *Source: GLOBOCAN 2012 (IARC) (8.6.2016)* Age grouping **Oral and Oropharyngeal Cancer** **0** **5** **10** **15** **20** **25** **0-14** **15-39** **40-44** **45-49** **50-54** **55-59** **60-64** **65-69** **70-74** **75+** **ASR (W)** GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013 # ## **Incidence by Age Group** **Oral and Oropharyngeal Cancer - ASR (W)** | Age grouping | ASR (W) | | :--- | :--- | | 0-14 | 0 | | 15-39 | ~1 | | 40-44 | ~3 | | 45-49 | ~5 | | 50-54 | ~9 | | 55-59 | ~14 | | 60-64 | ~19 | | 65-69 | ~22 | | 70-74 | ~24 | | 75+ | ~25 | *Source: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013* **Article** **Oral and oropharyngeal cancer in Oceania: Incidence, mortality, trends and gaps in public databases as presented to the Global Oral Cancer Forum** **Katherine Pollaers¹, Omar Kujan¹, Newell W Johnson² and Camile S Farah** **Table 3. Prevalence, incidence and mortality rates of lip, OCC-OPCs in Oceania (GLOBOCAN 2012).** <html> <body> <table> <thead> <tr> <td>Region</td> <td colspan="6">Incidence</td> <td colspan="6">Mortality</td> </tr> <tr> <td></td> <td colspan="2">Males</td> <td colspan="2">Females</td> <td colspan="2">Both sexes</td> <td colspan="2">Males</td> <td colspan="2">Females</td> <td colspan="2">Both sexes</td> </tr> <tr> <td></td> <td>Number</td> <td>ASR (W)</td> <td>Number</td> <td>ASR (W)</td> <td>Number</td> <td>ASR (W)</td> <td>Number</td> <td>ASR (W)</td> <td>Number</td> <td>ASR (W)</td> <td>Number</td> <td>ASR (W)</td> </tr> </thead> <tbody> <tr> <td>World</td> <td>314,106</td> <td>8.8</td> <td>128,654</td> <td>3.2</td> <td>442,760</td> <td>5.9</td> <td>175,538</td> <td>4.9</td> <td>65,920</td> <td>1.6</td> <td>241,458</td> <td>3.2</td> </tr> <tr> <td>Oceania</td> <td>2995</td> <td>12.7</td> <td>1511</td> <td>5.9</td> <td>4506</td> <td>9.2</td> <td>984</td> <td>4</td> <td>569</td> <td>2.1</td> <td>1553</td> <td>3</td> </tr> <tr> <td>Australia</td> <td>2060</td> <td>12.2</td> <td>886</td> <td>4.6</td> <td>2946</td> <td>8.3</td> <td>482</td> <td>2.6</td> <td>210</td> <td>0.9</td> <td>692</td> <td>1.7</td> </tr> <tr> <td>Fiji</td> <td>24</td> <td>5.7</td> <td>8</td> <td>1.8</td> <td>32</td> <td>3.8</td> <td>9</td> <td>2.9</td> <td>4</td> <td>0.9</td> <td>13</td> <td>1.8</td> </tr> <tr> <td>French Polynesia</td> <td>17</td> <td>11.8</td> <td>5</td> <td>3.4</td> <td>22</td> <td>7.7</td> <td>10</td> <td>7</td> <td>1</td> <td>0.6</td> <td>11</td> <td>3.9</td> </tr> <tr> <td>Guam</td> <td>5</td> <td>5.2</td> <td>0</td> <td>0</td> <td>5</td> <td>2.5</td> <td>2</td> <td>2</td> <td>0</td> <td>0</td> <td>2</td> <td>1</td> </tr> <tr> <td>New Caledonia</td> <td>20</td> <td>13.9</td> <td>3</td> <td>1.8</td> <td>23</td> <td>7.8</td> <td>11</td> <td>7.7</td> <td>5</td> <td>3.4</td> <td>16</td> <td>5.5</td> </tr> <tr> <td>New Zealand</td> <td>251</td> <td>7.9</td> <td>116</td> <td>3.1</td> <td>367</td> <td>5.4</td> <td>85</td> <td>2.4</td> <td>39</td> <td>0.9</td> <td>124</td> <td>1.6</td> </tr> <tr> <td>Papua New Guinea</td> <td>589</td> <td>34.8</td> <td>488</td> <td>21.7</td> <td>1077</td> <td>27.2</td> <td>372</td> <td>22.9</td> <td>308</td> <td>14</td> <td>680</td> <td>17.7</td> </tr> <tr> <td>Samoa</td> <td>2</td> <td>2.3</td> <td>0</td> <td>0</td> <td>2</td> <td>1.2</td> <td>0</td> <td>0</td> <td>0</td> <td>0</td> <td>0</td> <td>0</td> </tr> <tr> <td>Solomon Islands</td> <td>11</td> <td>6.5</td> <td>2</td> <td>1.5</td> <td>13</td> <td>4</td> <td>7</td> <td>4.7</td> <td>1</td> <td>0.8</td> <td>8</td> <td>2.7</td> </tr> <tr> <td>Vanuatu</td> <td>5</td> <td>6</td> <td>2</td> <td>3.2</td> <td>7</td> <td>4.6</td> <td>3</td> <td>4.6</td> <td>1</td> <td>1.6</td> <td>4</td> <td>3.1</td> </tr> </tbody> </table> </body> </html> OCC-OPC: oral cavity and oropharyngeal cancer; ASR: age-standardized rates. # ## **Oceania Incidence and Mortality Data (2012)** **Article: Oral and oropharyngeal cancer in Oceania: Incidence, mortality, trends and gaps in public databases as presented to the Global Oral Cancer Forum** *Katherine Pollaers¹, Omar Kujan¹, Newell W Johnson² and Camile S Farah* **Table 3. Prevalence, incidence and mortality rates of lip, OCC-OPCs in Oceania (GLOBOCAN 2012).** | Region | Incidence Males Number | Incidence Males ASR (W) | Incidence Females Number | Incidence Females ASR (W) | Incidence Both Sexes Number | Incidence Both Sexes ASR (W) | Mortality Males Number | Mortality Males ASR (W) | Mortality Females Number | Mortality Females ASR (W) | Mortality Both Sexes Number | Mortality Both Sexes ASR (W) | | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | | **World** | 314,106 | 8.8 | 128,654 | 3.2 | 442,760 | 5.9 | 175,538 | 4.9 | 65,920 | 1.6 | 241,458 | 3.2 | | **Oceania** | 2995 | 12.7 | 1511 | 5.9 | 4506 | 9.2 | 984 | 4 | 569 | 2.1 | 1553 | 3 | | **Australia** | 2060 | 12.2 | 886 | 4.6 | 2946 | 8.3 | 482 | 2.6 | 210 | 0.9 | 692 | 1.7 | | **Fiji** | 24 | 5.7 | 8 | 1.8 | 32 | 3.8 | 9 | 2.9 | 4 | 0.9 | 13 | 1.8 | | **French Polynesia** | 17 | 11.8 | 5 | 3.4 | 22 | 7.7 | 10 | 7 | 1 | 0.6 | 11 | 3.9 | | **Guam** | 5 | 5.2 | 0 | 0 | 5 | 2.5 | 2 | 2 | 0 | 0 | 2 | 1 | | **New Caledonia** | 20 | 13.9 | 3 | 1.8 | 23 | 7.8 | 11 | 7.7 | 5 | 3.4 | 16 | 5.5 | | **New Zealand** | 251 | 7.9 | 116 | 3.1 | 367 | 5.4 | 85 | 2.4 | 39 | 0.9 | 124 | 1.6 | | **Papua New Guinea** | 589 | 34.8 | 488 | 21.7 | 1077 | 27.2 | 372 | 22.9 | 308 | 14 | 680 | 17.7 | | **Samoa** | 2 | 2.3 | 0 | 0 | 2 | 1.2 | 0 | 0 | 0 | 0 | 0 | 0 | | **Solomon Islands** | 11 | 6.5 | 2 | 1.5 | 13 | 4 | 7 | 4.7 | 1 | 0.8 | 8 | 2.7 | | **Vanuatu** | 5 | 6 | 2 | 3.2 | 7 | 4.6 | 3 | 4.6 | 1 | 1.6 | 4 | 3.1 | *OCC-OPC: oral cavity and oropharyngeal cancer; ASR: age-standardized rates.* **Epidemiology of OSCC** * Over 95% of Oral Cancer are Squamous Cell Carcinomas * High mortality and morbidity. * Survival rate has not changed (50% for 5 years) * Over 60% of patients present locally or regionally advanced disease. * Trends in the age and sex groups # ## **Epidemiology of OSCC** - Over 95% of Oral Cancer are Squamous Cell Carcinomas - High mortality and morbidity. - Survival rate has not changed (50% for 5 years) - Over 60% of patients present locally or regionally advanced disease. - Trends in the age and sex groups Risk factors betelnut01 Cubanitos Premium Cigars Cubanitos Especiales Premium Cigars Premium Brand Cigarettes # # **Aetiology and Risk Factors** betelnut01 Cubanitos Premium Cigars Cubanitos Especiales Premium Cigars Premium Brand Cigarettes **"As an active substance, nicotine, on a** **milligram for milligram basis is 10 times** **more potent than heroin...."** **Sachs, DPL. Advances in smoking cessation** **treatment. In: Simmons, ed. Current** **Pulmonology. Chicago: Year book medical** **publishers, 1991; 12: 139 - 198.** # ## **Nicotine** > "As an active substance, nicotine, on a milligram for milligram basis is 10 times more potent than heroin...." > > **Sachs, DPL. Advances in smoking cessation treatment. In: Simmons, ed. Current Pulmonology. Chicago: Year book medical publishers, 1991; 12: 139 - 198.** Image of wine bottles labeled "Risk factors" – suggests alcohol as a potential health risk. # ## **Other Risk Factors (Images)** Image of wine bottles labeled "Risk factors" – suggests alcohol as a potential health risk. Microscopic images of viral particles (likely Norovirus). Microscopic images of viral particles (likely Norovirus). Image of various fresh vegetables, legumes, nuts, and grains. Image of various fresh vegetables, legumes, nuts, and grains. **ORAL CANCER** **> Cancer arises by progressive accumulation** **of genetic damage.** **> About 6-8 gene mutations are typical, each** **must confer a growth advantage on the** **cell.** # # **Pathogenesis** > Cancer arises by progressive accumulation of genetic damage. > > About 6-8 gene mutations are typical, each must confer a growth advantage on the cell. ```mermaid graph TD A[Accidental production of mutant cell] --> B[CELL PROLIFERATION] B --> C[Cell with 2 mutations] C --> D[CELL PROLIFERATION] D --> E[Cell with 3 mutations] E --> F[DANGEROUS CELL PROLIFERATION] ``` # ## **Genetic Damage Accumulation** ```mermaid graph TD A[Accidental production of mutant cell] --> B[CELL PROLIFERATION] B --> C[Cell with 2 mutations] C --> D[CELL PROLIFERATION] D --> E[Cell with 3 mutations] E --> F[DANGEROUS CELL PROLIFERATION] ``` ```mermaid graph TD subgraph CYTOSOL subgraph NUCLEUS p16("p16"):::nucleusColor cyclinD("cyclin D"):::nucleusColor Rb("Rb"):::nucleusColor E2F("E2F"):::nucleusColor changesingeneexpression(("changes in gene expression")) end WNT("WNT") cells("cells") Ecadherin("E-cadherin") extracellularMatrix("extracellular matrix") growthFactors("growth factors") integrins("integrins") receptorTyrosineKinases("receptor tyrosine kinases") hormones("hormones") survivalFactors("survival factors") antiGrowthFactors("anti-growth factors") APC("APC") betacatenin("β-catenin") TCF4("TCF4") Smads("Smads") p21("p21") DNAdamageSensor("DNA damage sensor") p53("p53") Myc("Myc") cellProliferation(("cell prol- iferation")) cellDeath(("cell death")) Bcl2("Bcl-2") abnormalitySensor("abnormality sensor") deathFactors("death factors") cytokines("cytokines") WNT --> APC cells --> Ecadherin Ecadherin --> betacatenin extracellularMatrix --> integrins growthFactors --> integrins integrins --> Ras receptorTyrosineKinases --> Ras hormones --> Ras survivalFactors --> Ras Ras --> Myc Ras --> changesingeneexpression APC --> betacatenin betacatenin --> TCF4 TCF4 --> changesingeneexpression antiGrowthFactors --> Smads Smads --> p21 DNA_damage_sensor --> p53 p53 --> p21 p53 --> cellDeath Myc --> cyclinD Myc --> changesingeneexpression cyclinD --> Rb Rb --> E2F E2F --> cellProliferation p21 --> cyclinD p21 --> E2F cellProliferation --> changesingeneexpression cellDeath --> changesingeneexpression Bcl2 --|inhibitory interaction| cellDeath abnormalitySensor --> cellDeath deathFactors --> cellDeath cytokines --> cellDeath end linkStyle 0 stroke:red linkStyle 1 stroke:red linkStyle 2 stroke:red linkStyle 3 stroke:red linkStyle 4 stroke:red linkStyle 5 stroke:red linkStyle 6 stroke:red linkStyle 7 stroke:red linkStyle 8 stroke:red linkStyle 9 stroke:red linkStyle 10 stroke:red linkStyle 11 stroke:red linkStyle 12 stroke:red linkStyle 13 stroke:red linkStyle 14 stroke:red linkStyle 15 stroke:red linkStyle 16 stroke:red linkStyle 17 stroke:red linkStyle 18 stroke:red linkStyle 19 stroke:red linkStyle 20 stroke:red linkStyle 21 stroke:red linkStyle 22 stroke:red linkStyle 23 stroke:red linkStyle 24 stroke:red linkStyle 25 stroke:red linkStyle 26 stroke:red linkStyle 27 stroke:red linkStyle 28 stroke:red linkStyle 29 stroke:red linkStyle 30 stroke:red linkStyle 31 stroke:red linkStyle 32 stroke:red linkStyle 33 stroke:red linkStyle 34 stroke:red linkStyle 35 stroke:red linkStyle 36 stroke:red linkStyle 37 stroke:red linkStyle 38 stroke:red linkStyle 39 stroke:red linkStyle 40 stroke:red linkStyle 41 stroke:red linkStyle 42 stroke:red linkStyle 43 stroke:red linkStyle 44 stroke:red linkStyle 45 stroke:red linkStyle 46 stroke:red linkStyle 47 stroke:red linkStyle 48 stroke:red linkStyle 49 stroke:red linkStyle 50 stroke:red linkStyle 51 stroke:red linkStyle 52 stroke:red linkStyle 53 stroke:red linkStyle 54 stroke:red linkStyle 55 stroke:red linkStyle 56 stroke:red linkStyle 57 stroke:red linkStyle 58 stroke:red linkStyle 59 stroke:red linkStyle 60 stroke:red linkStyle 61 stroke:red linkStyle 62 stroke:red linkStyle 63 stroke:red linkStyle 64 stroke:red linkStyle 65 stroke:red linkStyle 66 stroke:red linkStyle 67 stroke:red linkStyle 68 stroke:red linkStyle 69 stroke:red linkStyle 70 stroke:red linkStyle 71 stroke:red linkStyle 72 stroke:red linkStyle 73 stroke:red linkStyle 74 stroke:red linkStyle 75 stroke:red linkStyle 76 stroke:red linkStyle 77 stroke:red linkStyle 78 stroke:red linkStyle 79 stroke:red linkStyle 80 stroke:red linkStyle 81 stroke:red linkStyle 82 stroke:red linkStyle 83 stroke:red linkStyle 84 stroke:red linkStyle 85 stroke:red linkStyle 86 stroke:red linkStyle 87 stroke:red linkStyle 88 stroke:red linkStyle 89 stroke:red linkStyle 90 stroke:red linkStyle 91 stroke:red linkStyle 92 stroke:red classDef nucleusColor fill:#FFEDB3,stroke:#333,stroke-width:1px; ``` This is a diagram of cellular signaling pathways. # ## **Cellular Signaling Pathways Diagram** ```mermaid graph TD subgraph CYTOSOL subgraph NUCLEUS p16("p16"):::nucleusColor cyclinD("cyclin D"):::nucleusColor Rb("Rb"):::nucleusColor E2F("E2F"):::nucleusColor changesingeneexpression(("changes in gene expression")) end WNT("WNT") cells("cells") Ecadherin("E-cadherin") extracellularMatrix("extracellular matrix") growthFactors("growth factors") integrins("integrins") receptorTyrosineKinases("receptor tyrosine kinases") hormones("hormones") survivalFactors("survival factors") antiGrowthFactors("anti-growth factors") APC("APC") betacatenin("β-catenin") TCF4("TCF4") Smads("Smads") p21("p21") DNAdamageSensor("DNA damage sensor") p53("p53") Myc("Myc") cellProliferation(("cell prol- iferation")) cellDeath(("cell death")) Bcl2("Bcl-2") abnormalitySensor("abnormality sensor") deathFactors("death factors") cytokines("cytokines") WNT --> APC cells --> Ecadherin Ecadherin --> betacatenin extracellularMatrix --> integrins growthFactors --> integrins integrins --> Ras receptorTyrosineKinases --> Ras hormones --> Ras survivalFactors --> Ras Ras --> Myc Ras --> changesingeneexpression APC --> betacatenin betacatenin --> TCF4 TCF4 --> changesingeneexpression antiGrowthFactors --> Smads Smads --> p21 DNA_damage_sensor --> p53 p53 --> p21 p53 --> cellDeath Myc --> cyclinD Myc --> changesingeneexpression cyclinD --> Rb Rb --> E2F E2F --> cellProliferation p21 --> cyclinD p21 --> E2F cellProliferation --> changesingeneexpression cellDeath --> changesingeneexpression Bcl2 --|inhibitory interaction| cellDeath abnormalitySensor --> cellDeath deathFactors --> cellDeath cytokines --> cellDeath end linkStyle 0 stroke:red linkStyle 1 stroke:red linkStyle 2 stroke:red linkStyle 3 stroke:red linkStyle 4 stroke:red linkStyle 5 stroke:red linkStyle 6 stroke:red linkStyle 7 stroke:red linkStyle 8 stroke:red linkStyle 9 stroke:red linkStyle 10 stroke:red linkStyle 11 stroke:red linkStyle 12 stroke:red linkStyle 13 stroke:red linkStyle 14 stroke:red linkStyle 15 stroke:red linkStyle 16 stroke:red linkStyle 17 stroke:red linkStyle 18 stroke:red linkStyle 19 stroke:red linkStyle 20 stroke:red linkStyle 21 stroke:red linkStyle 22 stroke:red linkStyle 23 stroke:red linkStyle 24 stroke:red linkStyle 25 stroke:red linkStyle 26 stroke:red linkStyle 27 stroke:red linkStyle 28 stroke:red linkStyle 29 stroke:red linkStyle 30 stroke:red linkStyle 31 stroke:red linkStyle 32 stroke:red linkStyle 33 stroke:red linkStyle 34 stroke:red linkStyle 35 stroke:red linkStyle 36 stroke:red linkStyle 37 stroke:red linkStyle 38 stroke:red linkStyle 39 stroke:red linkStyle 40 stroke:red linkStyle 41 stroke:red linkStyle 42 stroke:red linkStyle 43 stroke:red linkStyle 44 stroke:red linkStyle 45 stroke:red linkStyle 46 stroke:red linkStyle 47 stroke:red linkStyle 48 stroke:red linkStyle 49 stroke:red linkStyle 50 stroke:red linkStyle 51 stroke:red linkStyle 52 stroke:red linkStyle 53 stroke:red linkStyle 54 stroke:red linkStyle 55 stroke:red linkStyle 56 stroke:red linkStyle 57 stroke:red linkStyle 58 stroke:red linkStyle 59 stroke:red linkStyle 60 stroke:red linkStyle 61 stroke:red linkStyle 62 stroke:red linkStyle 63 stroke:red linkStyle 64 stroke:red linkStyle 65 stroke:red linkStyle 66 stroke:red linkStyle 67 stroke:red linkStyle 68 stroke:red linkStyle 69 stroke:red linkStyle 70 stroke:red linkStyle 71 stroke:red linkStyle 72 stroke:red linkStyle 73 stroke:red linkStyle 74 stroke:red linkStyle 75 stroke:red linkStyle 76 stroke:red linkStyle 77 stroke:red linkStyle 78 stroke:red linkStyle 79 stroke:red linkStyle 80 stroke:red linkStyle 81 stroke:red linkStyle 82 stroke:red linkStyle 83 stroke:red linkStyle 84 stroke:red linkStyle 85 stroke:red linkStyle 86 stroke:red linkStyle 87 stroke:red linkStyle 88 stroke:red linkStyle 89 stroke:red linkStyle 90 stroke:red linkStyle 91 stroke:red linkStyle 92 stroke:red classDef nucleusColor fill:#FFEDB3,stroke:#333,stroke-width:1px; ``` This is a diagram of cellular signaling pathways. **Oral squamous cell carcinoma** * A long-standing white patch * A small exophytic growth (possibly with no ulceration) * A long-standing red patch * These lesions are generally painless # # **Clinical Features** # ## **Common Presentations of Oral Squamous Cell Carcinoma** - A long-standing white patch - A small exophytic growth (possibly with no ulceration) - A long-standing red patch - These lesions are generally painless Certain features should be viewed with suspicion <ul> <li>Ulceration</li> <li>Induration</li> <li>Fixation to underlying structures</li> <li>Bone destruction</li> </ul> # ## **Suspicious Features** Certain features should be viewed with **suspicion**: - Ulceration - Induration - Fixation to underlying structures - Bone destruction **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** An image showing the inside of a mouth with what appears to be oral lesions. An image showing the inside of a mouth with what appears to be oral lesions. An image of a patient's mouth with a lesion on the lip. In the bottom right corner, the letters **SCC** are visible. An image of a patient's mouth with a lesion on the lip. In the bottom right corner, the letters **SCC** are visible. Image of a man with a severe nasal injury. Image of a man with a severe nasal injury. # Histopathological features * Dysplastic stratified squamous epithelium that extends through the basement membrane and into the underlying fibrous connective tissue without attachment to the surface * Malignant epithelial cells show eosinophilic cytoplasm, hyperchromatic nuclei, pleomorphism, mitotic activity, individual cell keratinization and intercellular bridging * Superficial or microinvasion can be used to describe the earliest moment of invasion * Malignant epithelium can invade fibrous connective tissue in islands, cords or individual cells * Keratin pearls of round, eosinophilic, concentric layers of keratin can be seen and are associated with well differentiated tumors * 3 histologic grades for conventional squamous cell carcinoma include well, moderately and poorly differentiated based on amount of keratinization, mitotic activity, cellular and nuclear pleomorphism, pattern of invasion and host response # # **Histopathological Features** # ## **General Characteristics** - Dysplastic stratified squamous epithelium that extends through the basement membrane and into the underlying fibrous connective tissue without attachment to the surface - Malignant epithelial cells show eosinophilic cytoplasm, hyperchromatic nuclei, pleomorphism, mitotic activity, individual cell keratinization and intercellular bridging - Superficial or microinvasion can be used to describe the earliest moment of invasion - Malignant epithelium can invade fibrous connective tissue in islands, cords or individual cells - Keratin pearls of round, eosinophilic, concentric layers of keratin can be seen and are associated with well differentiated tumors - 3 histologic grades for conventional squamous cell carcinoma include well, moderately and poorly differentiated based on amount of keratinization, mitotic activity, cellular and nuclear pleomorphism, pattern of invasion and host response A histopathological slide showing tissue under a microscope, alongside a gross pathological specimen of a resected tissue. A histopathological slide showing tissue under a microscope, alongside a gross pathological specimen of a resected tissue. Histological slide showing squamous cell carcinoma with associated inflammation. Histological slide showing squamous cell carcinoma with associated inflammation. **Well-differentiated OSCC** **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** # ## **Differentiation Grades** # ### **Well-differentiated OSCC** **Moderately-differentiated OSCC** # ### **Moderately-differentiated OSCC** **Poorly-differentiated OSCC** **THE UNIVERSITY OF WESTERN AUSTRALIA** # ### **Poorly-differentiated OSCC** a jaw with teeth a jaw with teeth Dissected pelvic region with labeled anatomical structures. Dissected pelvic region with labeled anatomical structures. Midline section Midline section Histological image of squamous cell carcinoma, showing malignant epithelial cells invading the underlying connective tissue. Histological image of squamous cell carcinoma, showing malignant epithelial cells invading the underlying connective tissue. **Poorly differentiated** **squamous cell** **carcinoma** **Poorly differentiated squamous cell carcinoma** **Poorly differentiated SCC** **Poorly differentiated SCC** Histological image showing muscle tissue (pink bundles) infiltrated by tumor cells (purple clusters) and inflammatory cells (smaller purple dots). Histological image showing muscle tissue (pink bundles) infiltrated by tumor cells (purple clusters) and inflammatory cells (smaller purple dots). Microscopic view of squamous cell carcinoma with keratin pearls. Microscopic view of squamous cell carcinoma with keratin pearls. Cross-section of spinal cord with visible gray and white matter differentiation. Cross-section of spinal cord with visible gray and white matter differentiation. Two images side by side: a clinical photograph of a person's neck and face, and a microscopic image of tissue. Two images side by side: a clinical photograph of a person's neck and face, and a microscopic image of tissue. **Local imaging and metastatic work-up** * **MRI ± CT, PET scan (oral cavity and neck)** * **Chest X-ray and thoracic spiral CT** * **Esogastroscopy** # # **Diagnosis and Staging** # ## **Local imaging and metastatic work-up** - **MRI ± CT, PET scan (oral cavity and neck)** - **Chest X-ray and thoracic spiral CT** - **Esogastroscopy** **TNM staging** * TNM classification (AJCC Cancer Staging Manual, 9th edition) * The extent of the tumor (**T**) * The spread to nearby lymph **n**odes (**N**) * The spread (**m**etastasis) to distant sites (**M**) # ## **TNM staging** - TNM classification (AJCC Cancer Staging Manual, 9th edition) - The extent of the tumor (**T**) - The spread to nearby lymph **n**odes (**N**) - The spread (**m**etastasis) to distant sites (**M**) Photograph showing a radical bilateral neck resection with hemi-mandibulectomy and floor of the mouth. The neck lymph nodes are included because the tumour often spreads via the lymphatic system. **1023/07** Photograph showing a radical bilateral neck resection with hemi-mandibulectomy and floor of the mouth. The neck lymph nodes are included because the tumour often spreads via the lymphatic system. **1023/07** **TNM/AJCC** * Tis: Carcinoma in situ * T1: Tumor 2 cm or less in greatest dimension * T2: Tumor > 2 cm but ≤ 4 cm in greatest dimension * T3: Tumor > 4 cm in greatest dimension * T4 (lip) Tumor invades adjacent structures (through cortical bone, inferior alveolar nerve, floor of mouth, skin of face) * T4 (oral cavity) Tumor invades adjacent structures (through cortical bone, into deep muscle of tongue, maxillary sinus, skin.) # ## **TNM/AJCC Staging Details** # ### **T (Tumor)** - **Tis:** Carcinoma in situ - **T1:** Tumor 2 cm or less in greatest dimension - **T2:** Tumor > 2 cm but ≤ 4 cm in greatest dimension - **T3:** Tumor > 4 cm in greatest dimension - **T4 (lip)** Tumor invades adjacent structures (through cortical bone, inferior alveolar nerve, floor of mouth, skin of face) - **T4 (oral cavity)** Tumor invades adjacent structures (through cortical bone, into deep muscle of tongue, maxillary sinus, skin.) **TNM/AJCC** * N0: no regional node metastasis * Nx: regional nodes cannot be assessed * N1: single ipsilateral node, ≤ 3 cm * N2a: single ipsilateral node, > 3 cm and ≤ 6 cm * N2b: multiple ipsilateral nodes, ≤ 6 cm * N2c: controlateral or bilateral nodes, ≤ 6 cm * N3: node > 6 cm # ### **N (Node)** - **N0:** no regional node metastasis - **Nx:** regional nodes cannot be assessed - **N1:** single ipsilateral node, ≤ 3 cm - **N2a:** single ipsilateral node, > 3 cm and ≤ 6 cm - **N2b:** multiple ipsilateral nodes, ≤ 6 cm - **N2c:** controlateral or bilateral nodes, ≤ 6 cm - **N3:** node > 6 cm Patient's inflamed neck and upper chest area. Patient's inflamed neck and upper chest area. **TNM/AJCC** * **Mx:** Distant metastasis cannot be assessed * **M0:** No distant metastasis * **M1:** Distant metastasis # ### **M (Metastasis)** - **Mx:** Distant metastasis cannot be assessed - **M0:** No distant metastasis - **M1:** Distant metastasis - **metastasis** - **micromet** - **Incomplete excision** - **Extra-nodal spread** **3mm** **3722/06** **10mm+** **Medial and ventral margins involved** **6mm** **Total yield: 31nodes** # ## **Pathological Findings Example** - **metastasis** - **micromet** - **Incomplete excision** - **Extra-nodal spread** - **3mm** - **3722/06** - **10mm+** - **Medial and ventral margins involved** - **6mm** - **Total yield: 31nodes** **ORAL CANCER- FIVE YEAR SURVIVAL** ❖ **Stage I > 80%** ❖ **Stage II ~60%** ❖ **Stage III ~35%** ❖ **Stage IV < 15%** # # **Prognosis** # ## **Oral Cancer - Five Year Survival** - **Stage I:** > 80% - **Stage II:** ~60% - **Stage III:** ~35% - **Stage IV:** < 15% **Prevention of Head and Neck** **Cancer in Primary Care Practice** 1. Identify patients who use tobacco and alcohol products. 2. Counsel patients to stop using tobacco and alcohol products. 3. Maintain high index of suspicion. 4. Conduct comprehensive exams. 5. Attend to common symptoms. 6. Evaluate symptomatic patients. 7. Maintain close medical surveillance of patients in high-risk occupations. 8. Refer high-risk patients with persistent symptoms and no findings to a head and neck surgeon. # # **Prevention and Early Detection** # ## **Prevention of Head and Neck Cancer in Primary Care Practice** 1. Identify patients who use tobacco and alcohol products. 2. Counsel patients to stop using tobacco and alcohol products. 3. Maintain high index of suspicion. 4. Conduct comprehensive exams. 5. Attend to common symptoms. 6. Evaluate symptomatic patients. 7. Maintain close medical surveillance of patients in high-risk occupations. 8. Refer high-risk patients with persistent symptoms and no findings to a head and neck surgeon. **Factors Delaying the Diagnosis** **of Head and Neck Cancers** - Patient procrastination in seeking medical attention - Physician delay in diagnosis - Patient remains asymptomatic for a prolonged period # ## **Factors Delaying the Diagnosis of Head and Neck Cancers** - Patient procrastination in seeking medical attention - Physician delay in diagnosis - Patient remains asymptomatic for a prolonged period **Prevention strategies** * Late diagnosis contributes to advanced stage disease and poor prognosis * Smoking cessation and alcohol drinking * Early detection is so important in improving the survival rate * Oral cancer screening (insufficient evidence) Screening for oral cancer-a perspective from the Global Oral Cancer Forum. Speight PM, Epstein J, Kujan O, Lingen MW, Nagao T, Ranganathan K, Vargas P. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Jun;123(6):680-687. # ## **Prevention strategies** - Late diagnosis contributes to advanced stage disease and poor prognosis - Smoking cessation and alcohol drinking - Early detection is so important in improving the survival rate - Oral cancer screening (insufficient evidence) *Screening for oral cancer-a perspective from the Global Oral Cancer Forum.* *Speight PM, Epstein J, Kujan O, Lingen MW, Nagao T, Ranganathan K, Vargas P. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Jun;123(6):680-687.* **Prevention strategies** - Squamous cell carcinoma is a malignant epithelial tumour. If you have a practice which has 20,000 patients you would expect to see one case of the disease every year. Dentists are often more effective than medics in detecting the early stages of oral cancer - Squamous cell carcinoma is a malignant epithelial tumour. If you have a practice which has 20,000 patients you would expect to see one case of the disease every year. Dentists are often more effective than medics in detecting the early stages of oral cancer # Clinical tips **Figure 13.10 'Red flag' features of oral mucosal disease** * **oral ulcers that have lasted for more than 2 weeks** * **orals ulcers that recur** * **nontraumatic oral ulcers in children** * **pigmented lesions on the oral mucosa** * **red, white or mixed red and white lesions on the oral mucosa of unknown origin or with features of potentially malignant disease, such as:** * **induration** * **ulceration with rolled margins** * **fixation to underlying tissues** * **lesions in high-risk sites (eg lateral tongue, floor of mouth)** * **facial or oral paraesthesia** * **persistent oral mucosal discomfort with no obvious cause** * **lumps or swellings, including lymphadenopathy** * **swelling, pain or blockage of a salivary gland, suggestive of salivary gland disease (eg see Figure 13.9 for common causes of salivary gland swellings)** * **suspected allergy or adverse reaction to dental materials (eg oral lichenoid lesion)** * **dry mouth that is not adequately relieved with artificial salivary products and nonpharmacological methods** * **dry mouth caused by systemic disease** * **suspected oral manifestations of systemic disease (eg syphilis, Behçet syndrome, HIV, inflammatory bowel disease, lichen planus, pemphigoid)** * **lesions occurring in immunocompromised patients (eg patients with neutropenia or HIV infection)** 55 # ## **Clinical tips** **Figure 13.10 'Red flag' features of oral mucosal disease** - **oral ulcers that have lasted for more than 2 weeks** - **orals ulcers that recur** - **nontraumatic oral ulcers in children** - **pigmented lesions on the oral mucosa** - **red, white or mixed red and white lesions on the oral mucosa of unknown origin or with features of potentially malignant disease, such as:** - induration - ulceration with rolled margins - fixation to underlying tissues - lesions in high-risk sites (eg lateral tongue, floor of mouth) - **facial or oral paraesthesia** - **persistent oral mucosal discomfort with no obvious cause** - **lumps or swellings, including lymphadenopathy** - **swelling, pain or blockage of a salivary gland, suggestive of salivary gland disease (eg see Figure 13.9 for common causes of salivary gland swellings)** - **suspected allergy or adverse reaction to dental materials (eg oral lichenoid lesion)** - **dry mouth that is not adequately relieved with artificial salivary products and nonpharmacological methods** - **dry mouth caused by systemic disease** - **suspected oral manifestations of systemic disease (eg syphilis, Behçet syndrome, HIV, inflammatory bowel disease, lichen planus, pemphigoid)** - **lesions occurring in immunocompromised patients (eg patients with neutropenia or HIV infection)** 56 **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** A **Mucosa** B C **Buccal** **mucosa** D **Vestibule** **Anterior** **gingiva** **Gingiva** **Lip** **Posterior** **gingiva** **Mucosa** E **Hard** **palate** F **Tonsillar** **area** G **Ventral surface** **of tongue** H **Soft palate** **Floor of** **mouth** **Lateral border** **of tongue** 8 Steps of Oral Cancer Screening Challenges in the Early Diagnosis of Oral Cancer, Evidence Gaps and Strategies for Improvement: A Scoping Review of Systematic Reviews. Cancers (Basel). 2022 Oct 10;14(19):4967. # ## **8 Steps of Oral Cancer Screening** - **A:** Mucosa - **B:** Mucosa - **C:** Buccal mucosa - **D:** Vestibule, Anterior gingiva, Gingiva, Lip, Posterior gingiva - **E:** Hard palate - **F:** Tonsillar area - **G:** Ventral surface of tongue - **H:** Soft palate, Floor of mouth, Lateral border of tongue *Challenges in the Early Diagnosis of Oral Cancer, Evidence Gaps and Strategies for Improvement: A Scoping Review of Systematic Reviews. Cancers (Basel). 2022 Oct 10;14(19):4967.* Join at **slido.com** **#3723 218** 57 # # **Q&A Session** Join at **slido.com** **#3723 218** An illustration of doctors operating on a giant patient. An illustration of doctors operating on a giant patient. [[PAGE:1]] # # **Oral Cancer** **DENT4217 Oral Path Module** [[PAGE:2]] # # **Learning outcomes** - Oral cancer - Aetiology and pathogenesis - Clinical features - Histopathologic features - Diagnosis [[PAGE:3]] # # **Oral Malignant Neoplasms** - **Common:** OSCC - **Less common:** - Salivary gland tumours - Malignant melanoma - Lymphoma - Neoplasms of bone and connective tissue - Some odontogenic tumours - Maxillary antral carcinoma - Metastatic neoplasms - Kaposi sarcoma [[PAGE:4]] # # **Epidemiology and Statistics** # ## **Global Prevalence** Oral cancer ranks 12th among all cancers in prevalence worldwide (Khalili, 2008) and when combined with pharyngeal cancer, it ranks 6th (Warnakulasuriya, 2009). Fig. 1.4 The incidence and mortality of head and neck cancer estimated in 2012 of the highest 20 countries over the world | Country | Male (Incidence) | Female (Incidence) | | :--- | :--- | :--- | | India | 1000 | 500 | | United States of America | | | | China | | | | Pakistan | | | | Germany | | | | Japan | | | | Brazil | | | | Bangladesh | | | | Russian Federation | | | | France (metropolitan) | | | | United Kingdom | | | | Indonesia | | | | Spain | | | | Italy | | | | Thailand | | | | Canada | | | | Ukraine | | | | Poland | | | | Australia | | | | Mexico | | | *(Estimated numbers (x100), 5-year prevalence, Incidence)* *Source: GLOBOCAN 2012 (IARC) (6.6.2016)* # ## **Estimated Incidence Worldwide (2012)** Table 1.1 Estimated incidence of lip, oral cavity and oropharyngeal cancer worldwide (all ages, both sexes), data derived from GLOBOCAN 2012 | Population | Numbers | Crude rate | ASR (W) | Cumulative risk | |:---|:---|:---|:---|:---| | World | 300,373 | 4.3 | 4.0 | 0.45 | | More developed regions | 100,823 | 8.1 | 4.7 | 0.54 | | Less developed regions | 199,550 | 3.4 | 3.7 | 0.42 | | Very high human development | 92,338 | 8.0 | 4.8 | 0.54 | | High human development | 45,734 | 4.4 | 3.8 | 0.45 | | Medium human development | 121,240 | 3.4 | 3.3 | 0.38 | | Low human development | 40,954 | 3.1 | 5.2 | 0.59 | | WHO African region (AFRO) | 13,484 | 1.5 | 2.7 | 0.30 | | WHO Americas region (PAHO) | 49,200 | 5.2 | 4.1 | 0.48 | [[PAGE:5]] # ## **Incidence by Region (GLOBOCAN 2012)** **Cancer of the lip and oral cavity (Both sexes)** **Incidence ASR (Age-Standardized Rate)** - **5.1+** - **3.8-5.1** - **2.5-3.8** - **1.9-2.5** - **<1.9** - **No Data** *Source: GLOBOCAN 2012 (IARC)* [[PAGE:6]] # ## **Mortality by Region (GLOBOCAN 2012)** **Cancer of the lip and oral cavity (Both sexes)** **Mortality ASR (Age-Standardized Rate)** - **2.2+** - **1.6-2.2** - **1.1-1.0** - **0.67-1.1** - **<0.07** - **No Data** *Source: GLOBOCAN 2012 (IARC)* [[PAGE:7]] # ## **Incidence Projection (2035)** **Lip, oral cavity - Number of new cancers in 2035 (all ages)** - **Male:** 327,537 - **Female:** 167,360 *Effects considered: Incidence in 2012, Demographic effect* *Source: GLOBOCAN 2012 (IARC) (8.6.2016)* [[PAGE:8]] # ## **Mortality Projection (2035)** **Lip, oral cavity - Number of cancer deaths in 2035 (all ages)** - **Male:** 162,614 - **Female:** 80,272 *Effects considered: Mortality in 2012, Demographic effect* *Source: GLOBOCAN 2012 (IARC) (8.6.2016)* [[PAGE:9]] # ## **Incidence by Age Group** **Oral and Oropharyngeal Cancer - ASR (W)** | Age grouping | ASR (W) | | :--- | :--- | | 0-14 | 0 | | 15-39 | ~1 | | 40-44 | ~3 | | 45-49 | ~5 | | 50-54 | ~9 | | 55-59 | ~14 | | 60-64 | ~19 | | 65-69 | ~22 | | 70-74 | ~24 | | 75+ | ~25 | *Source: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013* [[PAGE:10]] # ## **Oceania Incidence and Mortality Data (2012)** **Article: Oral and oropharyngeal cancer in Oceania: Incidence, mortality, trends and gaps in public databases as presented to the Global Oral Cancer Forum** *Katherine Pollaers¹, Omar Kujan¹, Newell W Johnson² and Camile S Farah* **Table 3. Prevalence, incidence and mortality rates of lip, OCC-OPCs in Oceania (GLOBOCAN 2012).** | Region | Incidence Males Number | Incidence Males ASR (W) | Incidence Females Number | Incidence Females ASR (W) | Incidence Both Sexes Number | Incidence Both Sexes ASR (W) | Mortality Males Number | Mortality Males ASR (W) | Mortality Females Number | Mortality Females ASR (W) | Mortality Both Sexes Number | Mortality Both Sexes ASR (W) | | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | | **World** | 314,106 | 8.8 | 128,654 | 3.2 | 442,760 | 5.9 | 175,538 | 4.9 | 65,920 | 1.6 | 241,458 | 3.2 | | **Oceania** | 2995 | 12.7 | 1511 | 5.9 | 4506 | 9.2 | 984 | 4 | 569 | 2.1 | 1553 | 3 | | **Australia** | 2060 | 12.2 | 886 | 4.6 | 2946 | 8.3 | 482 | 2.6 | 210 | 0.9 | 692 | 1.7 | | **Fiji** | 24 | 5.7 | 8 | 1.8 | 32 | 3.8 | 9 | 2.9 | 4 | 0.9 | 13 | 1.8 | | **French Polynesia** | 17 | 11.8 | 5 | 3.4 | 22 | 7.7 | 10 | 7 | 1 | 0.6 | 11 | 3.9 | | **Guam** | 5 | 5.2 | 0 | 0 | 5 | 2.5 | 2 | 2 | 0 | 0 | 2 | 1 | | **New Caledonia** | 20 | 13.9 | 3 | 1.8 | 23 | 7.8 | 11 | 7.7 | 5 | 3.4 | 16 | 5.5 | | **New Zealand** | 251 | 7.9 | 116 | 3.1 | 367 | 5.4 | 85 | 2.4 | 39 | 0.9 | 124 | 1.6 | | **Papua New Guinea** | 589 | 34.8 | 488 | 21.7 | 1077 | 27.2 | 372 | 22.9 | 308 | 14 | 680 | 17.7 | | **Samoa** | 2 | 2.3 | 0 | 0 | 2 | 1.2 | 0 | 0 | 0 | 0 | 0 | 0 | | **Solomon Islands** | 11 | 6.5 | 2 | 1.5 | 13 | 4 | 7 | 4.7 | 1 | 0.8 | 8 | 2.7 | | **Vanuatu** | 5 | 6 | 2 | 3.2 | 7 | 4.6 | 3 | 4.6 | 1 | 1.6 | 4 | 3.1 | *OCC-OPC: oral cavity and oropharyngeal cancer; ASR: age-standardized rates.* [[PAGE:11]] # ## **Epidemiology of OSCC** - Over 95% of Oral Cancer are Squamous Cell Carcinomas - High mortality and morbidity. - Survival rate has not changed (50% for 5 years) - Over 60% of patients present locally or regionally advanced disease. - Trends in the age and sex groups [[PAGE:12]] # # **Aetiology and Risk Factors** betelnut01 Cubanitos Premium Cigars Cubanitos Especiales Premium Cigars Premium Brand Cigarettes [[PAGE:13]] # ## **Nicotine** > "As an active substance, nicotine, on a milligram for milligram basis is 10 times more potent than heroin...." > > **Sachs, DPL. Advances in smoking cessation treatment. In: Simmons, ed. Current Pulmonology. Chicago: Year book medical publishers, 1991; 12: 139 - 198.** [[PAGE:14]] # ## **Other Risk Factors (Images)** Image of wine bottles labeled "Risk factors" – suggests alcohol as a potential health risk. [[PAGE:15]] Microscopic images of viral particles (likely Norovirus). [[PAGE:16]] Image of various fresh vegetables, legumes, nuts, and grains. [[PAGE:17]] # # **Pathogenesis** > Cancer arises by progressive accumulation of genetic damage. > > About 6-8 gene mutations are typical, each must confer a growth advantage on the cell. [[PAGE:18]] # ## **Genetic Damage Accumulation** ```mermaid graph TD A[Accidental production of mutant cell] --> B[CELL PROLIFERATION] B --> C[Cell with 2 mutations] C --> D[CELL PROLIFERATION] D --> E[Cell with 3 mutations] E --> F[DANGEROUS CELL PROLIFERATION] ``` [[PAGE:19]] # ## **Cellular Signaling Pathways Diagram** ```mermaid graph TD subgraph CYTOSOL subgraph NUCLEUS p16("p16"):::nucleusColor cyclinD("cyclin D"):::nucleusColor Rb("Rb"):::nucleusColor E2F("E2F"):::nucleusColor changesingeneexpression(("changes in gene expression")) end WNT("WNT") cells("cells") Ecadherin("E-cadherin") extracellularMatrix("extracellular matrix") growthFactors("growth factors") integrins("integrins") receptorTyrosineKinases("receptor tyrosine kinases") hormones("hormones") survivalFactors("survival factors") antiGrowthFactors("anti-growth factors") APC("APC") betacatenin("β-catenin") TCF4("TCF4") Smads("Smads") p21("p21") DNAdamageSensor("DNA damage sensor") p53("p53") Myc("Myc") cellProliferation(("cell prol- iferation")) cellDeath(("cell death")) Bcl2("Bcl-2") abnormalitySensor("abnormality sensor") deathFactors("death factors") cytokines("cytokines") WNT --> APC cells --> Ecadherin Ecadherin --> betacatenin extracellularMatrix --> integrins growthFactors --> integrins integrins --> Ras receptorTyrosineKinases --> Ras hormones --> Ras survivalFactors --> Ras Ras --> Myc Ras --> changesingeneexpression APC --> betacatenin betacatenin --> TCF4 TCF4 --> changesingeneexpression antiGrowthFactors --> Smads Smads --> p21 DNA_damage_sensor --> p53 p53 --> p21 p53 --> cellDeath Myc --> cyclinD Myc --> changesingeneexpression cyclinD --> Rb Rb --> E2F E2F --> cellProliferation p21 --> cyclinD p21 --> E2F cellProliferation --> changesingeneexpression cellDeath --> changesingeneexpression Bcl2 --|inhibitory interaction| cellDeath abnormalitySensor --> cellDeath deathFactors --> cellDeath cytokines --> cellDeath end linkStyle 0 stroke:red linkStyle 1 stroke:red linkStyle 2 stroke:red linkStyle 3 stroke:red linkStyle 4 stroke:red linkStyle 5 stroke:red linkStyle 6 stroke:red linkStyle 7 stroke:red linkStyle 8 stroke:red linkStyle 9 stroke:red linkStyle 10 stroke:red linkStyle 11 stroke:red linkStyle 12 stroke:red linkStyle 13 stroke:red linkStyle 14 stroke:red linkStyle 15 stroke:red linkStyle 16 stroke:red linkStyle 17 stroke:red linkStyle 18 stroke:red linkStyle 19 stroke:red linkStyle 20 stroke:red linkStyle 21 stroke:red linkStyle 22 stroke:red linkStyle 23 stroke:red linkStyle 24 stroke:red linkStyle 25 stroke:red linkStyle 26 stroke:red linkStyle 27 stroke:red linkStyle 28 stroke:red linkStyle 29 stroke:red linkStyle 30 stroke:red linkStyle 31 stroke:red linkStyle 32 stroke:red linkStyle 33 stroke:red linkStyle 34 stroke:red linkStyle 35 stroke:red linkStyle 36 stroke:red linkStyle 37 stroke:red linkStyle 38 stroke:red linkStyle 39 stroke:red linkStyle 40 stroke:red linkStyle 41 stroke:red linkStyle 42 stroke:red linkStyle 43 stroke:red linkStyle 44 stroke:red linkStyle 45 stroke:red linkStyle 46 stroke:red linkStyle 47 stroke:red linkStyle 48 stroke:red linkStyle 49 stroke:red linkStyle 50 stroke:red linkStyle 51 stroke:red linkStyle 52 stroke:red linkStyle 53 stroke:red linkStyle 54 stroke:red linkStyle 55 stroke:red linkStyle 56 stroke:red linkStyle 57 stroke:red linkStyle 58 stroke:red linkStyle 59 stroke:red linkStyle 60 stroke:red linkStyle 61 stroke:red linkStyle 62 stroke:red linkStyle 63 stroke:red linkStyle 64 stroke:red linkStyle 65 stroke:red linkStyle 66 stroke:red linkStyle 67 stroke:red linkStyle 68 stroke:red linkStyle 69 stroke:red linkStyle 70 stroke:red linkStyle 71 stroke:red linkStyle 72 stroke:red linkStyle 73 stroke:red linkStyle 74 stroke:red linkStyle 75 stroke:red linkStyle 76 stroke:red linkStyle 77 stroke:red linkStyle 78 stroke:red linkStyle 79 stroke:red linkStyle 80 stroke:red linkStyle 81 stroke:red linkStyle 82 stroke:red linkStyle 83 stroke:red linkStyle 84 stroke:red linkStyle 85 stroke:red linkStyle 86 stroke:red linkStyle 87 stroke:red linkStyle 88 stroke:red linkStyle 89 stroke:red linkStyle 90 stroke:red linkStyle 91 stroke:red linkStyle 92 stroke:red classDef nucleusColor fill:#FFEDB3,stroke:#333,stroke-width:1px; ``` This is a diagram of cellular signaling pathways. [[PAGE:20]] # # **Clinical Features** # ## **Common Presentations of Oral Squamous Cell Carcinoma** - A long-standing white patch - A small exophytic growth (possibly with no ulceration) - A long-standing red patch - These lesions are generally painless [[PAGE:21]] # ## **Suspicious Features** Certain features should be viewed with **suspicion**: - Ulceration - Induration - Fixation to underlying structures - Bone destruction [[PAGE:22]] [[PAGE:23]] An image showing the inside of a mouth with what appears to be oral lesions. [[PAGE:24]] An image of a patient's mouth with a lesion on the lip. In the bottom right corner, the letters **SCC** are visible. [[PAGE:25]] Image of a man with a severe nasal injury. [[PAGE:26]] # # **Histopathological Features** # ## **General Characteristics** - Dysplastic stratified squamous epithelium that extends through the basement membrane and into the underlying fibrous connective tissue without attachment to the surface - Malignant epithelial cells show eosinophilic cytoplasm, hyperchromatic nuclei, pleomorphism, mitotic activity, individual cell keratinization and intercellular bridging - Superficial or microinvasion can be used to describe the earliest moment of invasion - Malignant epithelium can invade fibrous connective tissue in islands, cords or individual cells - Keratin pearls of round, eosinophilic, concentric layers of keratin can be seen and are associated with well differentiated tumors - 3 histologic grades for conventional squamous cell carcinoma include well, moderately and poorly differentiated based on amount of keratinization, mitotic activity, cellular and nuclear pleomorphism, pattern of invasion and host response [[PAGE:27]] A histopathological slide showing tissue under a microscope, alongside a gross pathological specimen of a resected tissue. [[PAGE:28]] Histological slide showing squamous cell carcinoma with associated inflammation. [[PAGE:29]] # ## **Differentiation Grades** # ### **Well-differentiated OSCC** [[PAGE:30]] # ### **Moderately-differentiated OSCC** [[PAGE:31]] # ### **Poorly-differentiated OSCC** [[PAGE:32]] a jaw with teeth [[PAGE:33]] Dissected pelvic region with labeled anatomical structures. [[PAGE:34]] Midline section [[PAGE:35]] Histological image of squamous cell carcinoma, showing malignant epithelial cells invading the underlying connective tissue. [[PAGE:36]] **Poorly differentiated squamous cell carcinoma** [[PAGE:37]] **Poorly differentiated SCC** [[PAGE:38]] Histological image showing muscle tissue (pink bundles) infiltrated by tumor cells (purple clusters) and inflammatory cells (smaller purple dots). [[PAGE:39]] Microscopic view of squamous cell carcinoma with keratin pearls. [[PAGE:40]] Cross-section of spinal cord with visible gray and white matter differentiation. [[PAGE:41]] Two images side by side: a clinical photograph of a person's neck and face, and a microscopic image of tissue. [[PAGE:42]] # # **Diagnosis and Staging** # ## **Local imaging and metastatic work-up** - **MRI ± CT, PET scan (oral cavity and neck)** - **Chest X-ray and thoracic spiral CT** - **Esogastroscopy** [[PAGE:43]] # ## **TNM staging** - TNM classification (AJCC Cancer Staging Manual, 9th edition) - The extent of the tumor (**T**) - The spread to nearby lymph **n**odes (**N**) - The spread (**m**etastasis) to distant sites (**M**) [[PAGE:44]] Photograph showing a radical bilateral neck resection with hemi-mandibulectomy and floor of the mouth. The neck lymph nodes are included because the tumour often spreads via the lymphatic system. **1023/07** [[PAGE:45]] # ## **TNM/AJCC Staging Details** # ### **T (Tumor)** - **Tis:** Carcinoma in situ - **T1:** Tumor 2 cm or less in greatest dimension - **T2:** Tumor > 2 cm but ≤ 4 cm in greatest dimension - **T3:** Tumor > 4 cm in greatest dimension - **T4 (lip)** Tumor invades adjacent structures (through cortical bone, inferior alveolar nerve, floor of mouth, skin of face) - **T4 (oral cavity)** Tumor invades adjacent structures (through cortical bone, into deep muscle of tongue, maxillary sinus, skin.) [[PAGE:46]] # ### **N (Node)** - **N0:** no regional node metastasis - **Nx:** regional nodes cannot be assessed - **N1:** single ipsilateral node, ≤ 3 cm - **N2a:** single ipsilateral node, > 3 cm and ≤ 6 cm - **N2b:** multiple ipsilateral nodes, ≤ 6 cm - **N2c:** controlateral or bilateral nodes, ≤ 6 cm - **N3:** node > 6 cm [[PAGE:47]] Patient's inflamed neck and upper chest area. [[PAGE:48]] # ### **M (Metastasis)** - **Mx:** Distant metastasis cannot be assessed - **M0:** No distant metastasis - **M1:** Distant metastasis [[PAGE:49]] # ## **Pathological Findings Example** - **metastasis** - **micromet** - **Incomplete excision** - **Extra-nodal spread** - **3mm** - **3722/06** - **10mm+** - **Medial and ventral margins involved** - **6mm** - **Total yield: 31nodes** [[PAGE:50]] # # **Prognosis** # ## **Oral Cancer - Five Year Survival** - **Stage I:** > 80% - **Stage II:** ~60% - **Stage III:** ~35% - **Stage IV:** < 15% [[PAGE:51]] # # **Prevention and Early Detection** # ## **Prevention of Head and Neck Cancer in Primary Care Practice** 1. Identify patients who use tobacco and alcohol products. 2. Counsel patients to stop using tobacco and alcohol products. 3. Maintain high index of suspicion. 4. Conduct comprehensive exams. 5. Attend to common symptoms. 6. Evaluate symptomatic patients. 7. Maintain close medical surveillance of patients in high-risk occupations. 8. Refer high-risk patients with persistent symptoms and no findings to a head and neck surgeon. [[PAGE:52]] # ## **Factors Delaying the Diagnosis of Head and Neck Cancers** - Patient procrastination in seeking medical attention - Physician delay in diagnosis - Patient remains asymptomatic for a prolonged period [[PAGE:53]] # ## **Prevention strategies** - Late diagnosis contributes to advanced stage disease and poor prognosis - Smoking cessation and alcohol drinking - Early detection is so important in improving the survival rate - Oral cancer screening (insufficient evidence) *Screening for oral cancer-a perspective from the Global Oral Cancer Forum.* *Speight PM, Epstein J, Kujan O, Lingen MW, Nagao T, Ranganathan K, Vargas P. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Jun;123(6):680-687.* [[PAGE:54]] - Squamous cell carcinoma is a malignant epithelial tumour. If you have a practice which has 20,000 patients you would expect to see one case of the disease every year. Dentists are often more effective than medics in detecting the early stages of oral cancer [[PAGE:55]] # ## **Clinical tips** **Figure 13.10 'Red flag' features of oral mucosal disease** - **oral ulcers that have lasted for more than 2 weeks** - **orals ulcers that recur** - **nontraumatic oral ulcers in children** - **pigmented lesions on the oral mucosa** - **red, white or mixed red and white lesions on the oral mucosa of unknown origin or with features of potentially malignant disease, such as:** - induration - ulceration with rolled margins - fixation to underlying tissues - lesions in high-risk sites (eg lateral tongue, floor of mouth) - **facial or oral paraesthesia** - **persistent oral mucosal discomfort with no obvious cause** - **lumps or swellings, including lymphadenopathy** - **swelling, pain or blockage of a salivary gland, suggestive of salivary gland disease (eg see Figure 13.9 for common causes of salivary gland swellings)** - **suspected allergy or adverse reaction to dental materials (eg oral lichenoid lesion)** - **dry mouth that is not adequately relieved with artificial salivary products and nonpharmacological methods** - **dry mouth caused by systemic disease** - **suspected oral manifestations of systemic disease (eg syphilis, Behçet syndrome, HIV, inflammatory bowel disease, lichen planus, pemphigoid)** - **lesions occurring in immunocompromised patients (eg patients with neutropenia or HIV infection)** [[PAGE:56]] # ## **8 Steps of Oral Cancer Screening** - **A:** Mucosa - **B:** Mucosa - **C:** Buccal mucosa - **D:** Vestibule, Anterior gingiva, Gingiva, Lip, Posterior gingiva - **E:** Hard palate - **F:** Tonsillar area - **G:** Ventral surface of tongue - **H:** Soft palate, Floor of mouth, Lateral border of tongue *Challenges in the Early Diagnosis of Oral Cancer, Evidence Gaps and Strategies for Improvement: A Scoping Review of Systematic Reviews. Cancers (Basel). 2022 Oct 10;14(19):4967.* [[PAGE:57]] # # **Q&A Session** Join at **slido.com** **#3723 218** [[PAGE:58]] An illustration of doctors operating on a giant patient.