• Radicular/periapical cyst is the most common odontogenic cyst and represents 50-60% of all jaw cysts.

• This cyst is inflammatory in origin. It is believed to develop from proliferating rests of Malassez in the periapical region.

• Radicular cyst usually occurs in the periapical region as a sequel to dental caries causing pulpal necrosis. It could also arise as a result of tooth fracture causing necrosis of the pulp.

• The cyst may be sometimes found on the lateral aspects of the roots in relation to lateral accessory root canals – called lateral radicular cyst.

PATHOGENESIS

• When infection (from the carious tooth) seeps through to the periapical region from an overlying tooth, a mass of reparative granulation tissue forms (provided the infection is chronic) as a defensive reaction to this microbial infection. This is called a periapical granuloma.

• The chronic inflammation may induce proliferation of the rests of Malassez in the periapical granuloma (initiation phase).

• A mass of cells is formed as a result of this proliferation. However, the cells at the centre of this mass do not receive nutrition and undergo liquefactive necrosis (cyst formation phase). This forms a cavity at the centre filled with fluid and lined with cells at the periphery.

• The cyst may then expand by osmosis and bone resorption (expansion phase).

The most popular theory of cyst formation phase is that (the one explained above)

- Cells (of Malassez) proliferate --> form a mass of cells -> cells in the centre are away from the nutrients provided by the connective tissue --> undergo ischaemic liquefactive necrosis. This creates a central cavity surrounded by a viable epithelium.

However, there are also other schools of thought (refer video, refer reference quoted)

- Degeneration of the central cells (in the proliferated mass of cells)--> due to an immunologic reaction or autolysis (as opposed to ischaemic necrosis due to lack of nutrients). Such degenerations happen in the epithelial islands (proliferated masses of cells) in different parts of the connective tissue and may coalesce to form a larger (single) cavity!

You could refer the chapter on “Radicular cyst” in the book “Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4th ed. Blackwell Munksgaard; 2007” for further details.

CLINICAL FEATURES

• Radicular cysts may occur at any age but appears to occur more often in people aged 30 to 60 years.

• Frequency of sites involved maxillary anteriors > maxillary posteriors > mandibular posteriors > mandibular anteriors.

• Very seldom are deciduous teeth involved.

• Involved or associated tooth is non-vital and does to respond to vitality tests.

• Radicular cysts are usually small and asymptomatic; they may be rarely painful and large causing bony expansion.

RADIOLOGY FEATURES

• Radicular cyst shows a round to ovoid radiolucency with a well corticated radiopaque rim.

• Associated tooth shows a loss of lamina dura.

• There may be resorption of roots of associated and adjacent teeth.

• It is not possible to differentiate between a radicular cyst and periapical granuloma radiographically (though a radicular cyst is usually bigger than a periapical granuloma).

HISTOPATHOLOGY FEATURES

• The epithelial lining:

  1. is stratified squamous and of variable thickness, usually 6-20 cell layers thick.

  2. is proliferative and may show an arcading pattern.

  3. may also, not show arcading in focal areas and may be simple stratified squamous.

• Rushton bodies or hyaline bodies are eosinophilic structures found rarely in the epithelium. These structures may be linear, concentric, curved or hairpin shaped.

• The radicular cyst usually shows a moderately to severely inflamed connective tissue having lymphocytes plasma cells and macrophages.

• Many radicular cysts show focal areas of numerous clefts called cholesterol clefts in the connective tissue.

TREATMENT

• A thorough root canal therapy of the associated tooth.

• Extraction of the tooth with curettage of the periapical tissue.

• If the size of the lesion is too big for conventional endodontic therapy, an endodontic surgery is performed and the cyst removed.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• Radicular/periapical cyst is the most common odontogenic cyst and represents 50-60% of all jaw cysts.

• This cyst is inflammatory in origin. It is believed to develop from proliferating rests of Malassez in the periapical region.

• Frequency of sites involved maxillary anteriors > maxillary posteriors > mandibular posteriors > mandibular anteriors.

• Involved or associated tooth is non-vital and does to respond to vitality tests.

• It is not possible to differentiate between a radicular cyst and periapical granuloma radiographically.

• The epithelium is proliferative and may show an arcading pattern (histopathology).

• Rushton bodies or hyaline bodies are eosinophilic structures found rarely in the epithelium.

• Rushton bodies or hyaline bodies are eosinophilic structures found rarely in the epithelium. These structures may be linear, concentric, curved or hairpin shaped.

QUESTIONS? BRING 'EM ON!!

1. What is an “apical pocket cyst”? Is it the same as a “bay cyst”?

Answer

Based on the relationship a radicular cyst shares with its associated tooth, there are two types of radicular cysts.

One type has a lumen or a cavity totally enclosed by the epithelial lining and this type is called the “apical true cyst”. This type is self-sustaining and could continue to grow if not curetted thoroughly.

The second type has its lumen or cavity in continuity with the root canal. That is, this cyst has its epithelium attached with the root apex, and is continuous with the root canal through its open lumen. This type is called the “apical pocket cyst” or “bay cyst”. Since this cyst is open it continues to grow, as long as bacteria and necrotic debris continue to seep through the canal and would definitely regress/disappear on extracting or endodontically treating the tooth.

2. Is there any other theory explaining the formation of radicular cyst (other than the one explained above)?

The initiation phase is followed by the cyst formation phase.

The most popular theory of cyst formation phase is that

• Cells (of Malassez) proliferate --> form a mass of cells -> cells in the centre are away from the nutrients provided by the connective tissue --> undergo ischaemic liquefactive necrosis. This creates a central cavity surrounded by a viable epithelium.

However, there are also other schools of thought

• Degeneration of the central cells (in the proliferated mass of cells)--> due to an immunologic reaction or autolysis (as opposed to ischaemic necrosis due to lack of nutrients). Such degenerations happen in the epithelial islands (proliferated masses of cells) in different parts of the connective tissue and may coalesce to form a larger (single) cavity!

You could refer the chapter on “Radicular cyst” in the book “Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4th ed. Blackwell Munksgaard; 2007” for further details.

3. Why do you think there may be cholesterol clefts formed in the connective tissue?

Answer

Cholesterol clefts are formed due to accumulation of cholesterol in the connective tissue, which then gets dissolved out during histologic preparations forming clefts. These cholesterol accumulations are hypothesized to be derived from the cell walls of disintegrating red blood cells, lymphocytes, plasma cells and macrophages.

📖REFERENCES AND FURTHER READING

1. Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4 th ed. Blackwell Munksgaard; 2007.

2. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

3. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

4. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

5. Sapp JP, Eversole LR, Wysocki GP. Contemporary Oral and Maxillofacial Pathology. 2 nd ed. Mosby; 2004.

* Please note there is a correction at 4:51 - FADD binds to FAS ligands and not to FAS receptors. The orange diagram where FADD is bound to, is the FAS-L and the yellow diagram is the FAS-R. Also explained in the notes below.

It is a prerequisite to have an awareness/knowledge of the basics of General Pathology, in order to better comprehend the pathology of oral diseases. The basics would immensely help your understanding of Oral Pathology and Medicine.

WHAT IS APOPTOSIS?

• Apoptosis, also called “programmed cell death” is the process where the cell regulates its own death through the production of certain enzymes.

• These enzymes cause degradation of nuclear and cytoplasmic DNA and the cell breaks into fragments called apoptotic bodies. Apoptotic bodies are then gobbled up by phagocytes.

WHAT COULD TRIGGER APOPTOSIS?

• Apoptosis could be triggered by factors such as infections, especially viral infections, misfolding of proteins due to mutations and DNA damage due to mutation, radiation, hypoxia and free radicals.

• Apart from pathologic factors inducing programmed cell death, apoptosis is also a homeostatic mechanism, where cells that are not needed are killed, thereby maintaining a steady state population of cells.

MORPHOLOGICAL CHANGES DURING APOPTOSIS

• During apoptosis, the cell undergoes certain morphologic changes that can be seen in light and electron microscopy.

• The cell shrinks and becomes smaller in size. The cytoplasm and organelles become tightly packed. The nuclear chromatin shrinks and becomes condensed (usually peripherally – best seen in electron microscopy), a process called pyknosis.

• Following this, chromatin material undergoes karyorrhexis, i.e it disintegrates and becomes fragmented.

• Under the microscope, a cell undergoing apoptosis would appear shrunken, with a dense eosinophilic cytoplasm and small clumps of hematoxophilic chromatin material.

• Further, the cell starts to form blebs on its surface and starts to break off into small fragments called apoptotic bodies. These apoptotic bodies have portions of cytoplasm, organelles and nuclear fragments of the cell.

• It is important to understand that apoptosis does not elicit inflammation, unlike another form of cell death called necrosis. This is because, apoptotic bodies have an intact plasma membrane and prevent any content from leaking out into the interstitial space. Also, apoptotic bodies are quickly recognized by phagocytes and removed from the environment.

MECHANISMS OF APOPTOSIS

• A cell can undergo apoptosis due to several reasons and depending on the etiologic factors may have 3 different pathways of initiating cell death.

• Apoptosis could be initiated by signals from the intrinsic pathway, the extrinsic pathway and the perforin/granzyme pathway.

Intrinsic pathway

• In the intrinsic pathway, mitochondria become leaky and ooze out proteins called cytochrome C, which initiate apoptosis.

• Usually the cytoplasm and mitochondrial membrane harbour proteins called Bcl-2 and Bcl-x which are anti-apoptotic and preserve the integrity of the mitochondrial membrane, preventing apoptotic proteins from leaking into the cytoplasm.

• However, in the absence of a growth signal, or insults due to radiation or protein misfolding, stress proteins called “BH3 only” proteins are stimulated. “BH3 only” proteins comprising of Bim, Bid and Bad proteins block the function of Bcl-2 and Bcl-x.

• These proteins further activate two pro-apoptotic effectors called Bax and Bak, which create channels in the mitochondrial membrane, allowing intra-mitochondrial proteins like cytochrome C to leak!

• Cytochrome C, in the cytoplasm, binds with a protein called Apaf – 1 (Apoptosis activating factor -1) to form a complex called “apoptosome”.

• Apoptosome binds with Caspase 9 and begins to cleave and activate adjacent caspase-9 molecules.

• Caspase 9 is an initiator caspase and activated Caspase 9 molecules activate executioner Caspases 3 and 6 leading to apoptosis of the cell.

Extrinsic pathway and Granzyme/Perforin pathway

• Cytotoxic T lymphocytes or CD8 T cells cause apoptosis of infected cells or tumor cells by FasL and Fas/death receptor interaction.

• Many cell types express a receptor called the Fas receptor and cytotoxic T cells express FasL.

• Cytotoxic T cells thus bind to the Fas receptor on tumor cells or infected cells through their FasL.

• This interaction may produce apoptotic signals through two pathways – the extrinsic or the Granzyme/Perforin pathway.

• The extrinsic pathway involves binding of an adapter protein called Fas-associated death domain (FADD) to the cytoplasmic end of at least 3-4 Fas ligands.

CORRECTION!

Please note there is a correction in the diagram below - FADD binds to FAS ligands and not to FAS receptors. The orange diagram where FADD is bound to, is the FAS-L and the yellow diagram is the FAS-R

• This then binds with caspase 8, an initiator caspase, which gets cleaved to become active. The active caspase 8 further activates other caspase 8 molecules. Caspase 8 moleules activate executioner Caspases 3 and 6 leading to apoptosis of the cell.

• At times the Granzyme/Perforin pathway is initiated on FasL/Fas receptor interaction.

• T cells release perforins, which form trans-membrane pores, through which granzymes, another protein secreted by T-cells, enter.

• Granzymes, could either directly activate executioner caspase molecules 3 or cause DNA cleaving, leading to apoptosis.

EXECUTION

• Executioner caspases 3 and 6 cause degradation of chromosomal DNA and also degradation of cytoskeletal proteins, which cause the morphological changes such as nuclear fragmentation and cellular shrinkage respectively.

• However, it is not yet known what causes changes like cellular blebs and apoptotic bodies.

• Apoptotic bodies are coated with a phospholipid called phosphotidylserine, which is recognised by phagocyte receptors.

• Also, apoptotic bodies may be coated with opsonins like antibody IgG or complement proteins like C3b which are recognised by phagocytes thus facilitating rapid phagocytosis of apoptotic bodies.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• Apoptosis, also called “programmed cell death” is the process where the cell regulates its own death through the production of certain enzymes.

• Apoptosis could be triggered by factors such as infections, especially viral infections, misfolding of proteins due to mutations and DNA damage due to mutation, radiation, hypoxia and free radicals.

• Apoptosis is also a homeostatic mechanism.

• The nuclear chromatin shrinks and becomes condensed (usually peripherally – best seen in electron microscopy), a process called pyknosis.

• Chromatin material undergoes karyorrhexis, i.e it disintegrates and becomes fragmented.

• Cell starts to form blebs on its surface and starts to break off into small fragments called apoptotic bodies.

• It is important to understand that apoptosis does not elicit inflammation, unlike another form of cell death called necrosis.

• Apoptosis could be initiated by signals from the intrinsic pathway, the extrinsic pathway and the perforin/granzyme pathway.

• “BH3 only” proteins comprising of Bim, Bid and Bad proteins block the function of Bcl-2 and Bcl-x.

• Caspase 9 is an initiator caspase and activated Caspase 9 molecules activate executioner Caspases 3 and 6 leading to apoptosis of the cell.

• Executioner caspases 3 and 6 cause degradation of chromosomal DNA and also degradation of cytoskeletal proteins, which cause the morphological changes such as nuclear fragmentation and cellular shrinkage respectively.

📖REFERENCES AND FURTHER READING

1. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins Basic Pathology. 10^th ed. Elsevier; 2018.

2. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran – Pathologic Basis of Disease. 8^th Edition. Saunders Elsevier; 2010.

3. Abbas AK, Litchman AH, Pillai S. Cellular and Molecular Immunology. 8^th Edition. Saunders Elsevier; 2015.

4. Elmore S. Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol. 2007; 35(4): 495–516.

5. Apoptosis and Signal Transduction. Available at https://www.wehi.edu.au/wehi-tv/apoptosis-and-signal-transduction.

6. Apoptosis. Available at http://www.onkoview.com/das-buch/kapitel-7/die-apoptose.html.

👉 hackdentistry.substack.com,

instead of hackdentistry.com.

This is a temporary change while some behind-the-scenes updates are in progress.

The site will be back on hackdentistry.com soon.

Also since there is a lot of material to be updated, I will be gradually adding material every week and update the open free archive of hackdentistry.

Cheers

Sanketh

• Odontogenic keratocyst (OKC) is the second most common developmental odontogenic cyst after dentigerous cyst. It makes up around 10% of all odontogenic cysts occurring in the oral cavity.

• This cyst is believed to develop from --> a) from the rests of the dental lamina and b) extensions of the basal cells from the overlying epithelium (“basal cell hamartias” or “basal cell offshoots”).

• It is called odontogenic keratocyst because it is “odontogenic” in origin and the cyst lumen is filled with “keratin”.

• OKC has an aggressive and destructive behavior as compared to other odontogenic cysts. Also, some OKCs have been reported to have genetic mutations in the PTCH1 and P53 genes giving it a greater growth potential.

• Hence, many pathologists considered OKC to be neoplastic. The 2005 World Health Organization (WHO) monograph on Head and Neck tumors classified it as an odontogenic tumor and named it “Keratocystic odontogenic tumor (KCOT)” in 2005.

💡RECENT UPDATES

The WHO consensus group in 2017, have however reinstated the name Odontogenic keratocyst and have reclassified the lesion as an odontogenic cyst. The group felt there was insufficient evidence to support its neoplastic nature.

CLINICAL FEATURES

• OKC predominantly occurs in the second and third decades of life.

• Has a slight male predilection.

• Predominantly occurs in the mandible usually in the third molar-ramus area.

• OKCs may range from being small and asymptomatic, to large lesions causing swelling and pain.

• A characteristic feature of OKC is its antero-posterior growth within the marrow cavity of the bone, causing no bone expansion despite its size.

• OKC has been reported to be associated with nevoid basal cell carcinoma syndrome or Gorlin syndrome. At least 90% of patients with this syndrome have been reported to have multiple OKCs.

RADIOLOGY FEATURES

• OKC does not have a characteristic radiographic appearance. It may mostly show a unilocular radiolucency though large lesions may appear mutlilocular.

• Around 25-40% of OKCs are associated with an unerupted tooth, showing a pericoronal radiolucency mimicking a dentigerous cyst.

• Large lesions may show buccal cortical expansion.

HISTOPATHOLOGY FEATURES

• The epithelial lining is composed of:

  1. stratified squamous epithelium usually 6-10 cells in thickness.

  2. corrugated or wavy parakeratinized layer

  3. cuboidal to columnar basal cell layer, that is palisaded, described as having a picket fence or tomb stone appearance.

• The epithelium does not have a prominent granular layer as present in orthokeratinized odontogenic cyst (OOC) (a factor differentiating OKC from OOC).

• The fibrous wall/connective tissue may harbour satellite cysts, cords or islands of odontogenic epithelium.

• The epithelium- connective tissue interface is flat and has no rete ridges.

• The lumen may contain a straw colored clear fluid or a cheesy material that represents keratin under the microscope.

💡OKC HAS A HIGH RECURRENCE RATE!

- Incomplete removal of OKC may lead to development of new cysts due to the retained satellite cysts and odontogenic islands or rests in the cyst wall.

- The epithelial lining is thin and friable, and may be difficult to completely remove (during treatment) when cysts are large. The leftover epithelium may give rise to the development of a new cyst.

TREATMENT

• OKCs are aggressive and have high recurrence rates (an average of 30%). It is thus very important to completely remove them.

• Peripheral ostectomy along with chemical cauterization (Carnoy’s solution) of the bone after removal of the cyst is recommended.

• Large OKCs can also be reduced in size by decompression and subsequently removed.

QUESTIONS? BRING 'EM ON!!

1. Orthokeratinized odontogenic cyst (OOC) is a variant of OKC. Is this true?

2. Would OKC show its characteristic histopathology picture if it was infected/inflamed?

3. Can OKC undergo a malignant transformation to squamous cell carcinoma?

4. The basal epithelial cells are cuboidal to columnar and palisaded, described as having a “tomb stone appearance”. Can you recollect any other lesion of the oral cavity, whose histology also shows basal cells having a tombstone appearance?

ANSWERS

1. Nope, OOC is not a variant of OKC!

   Orthokeratinized odontogenic cyst (OOC) was first described as an orthokeratinizing variant of odontogenic keratocyst (OKC) in 1981. The basis of this distinction was the difference in its histopathology and its reduced chances of recurrence as compared to OKC.

   It is now known and accepted that OOC is a distinct clinic-pathologic entity on its own. In fact it has been listed as a developmental odontogenic cyst in the recent (2017) WHO classification of odontogenic cysts.

2. It wouldn’t!

   In the presence of intense inflammation, the overlying epithelium may lose its characteristic features, wherein parakeratinization and the palisading of basal layer are lost. Also, the epithelium may develop rete ridges. In such cases it would be difficult to make a diagnosis.

3. Yes, OKC has been reported to undergo malignant transformation to oral squamous cell carcinoma although very rarely.

4. The epithelium in pemphigus vulgaris shows acantholysis (loss of cohesion between the epithelial cells) in the parabasal layers with the basal layers being attached to the basement membrane. The basal cells resemble a “row of tombstones”.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• This cyst is believed to develop from --> a) from the rests of the dental lamina and b) extensions of the basal cells from the overlying epithelium (“basal cell hamartias” or “basal cell offshoots”).

• OKC has an aggressive and destructive behaviour as compared to other odontogenic cysts. Also, some OKCs have been reported to have genetic mutations in the PTCH1 and P53 genes giving it a greater growth potential.

• Predominantly occurs in the mandible usually in the third molar-ramus area.

• A characteristic feature of OKC is its antero-posterior growth within the marrow cavity of the bone, causing no bone expansion despite its size.

• OKC has been reported to be associated with nevoid basal cell carcinoma syndrome or Gorlin syndrome.

• The epithelium does not have a prominent granular layer as present in orthokeratinized odontogenic cyst (OOC) (a factor differentiating OKC from OOC).

• The fibrous wall/connective tissue may harbour satellite cysts, cords or islands of odontogenic epithelium.

• OKC has a high recurrence rate (an average of 30%).

• Incomplete removal of OKC may lead to development of new cysts due to the retained satellite cysts and odontogenic islands or rests in the cyst wall.

• The epithelial lining is thin and friable, and may be difficult to completely remove (during treatment) when cysts are large. The leftover epithelium may give rise to the development of a new cyst.

• Peripheral ostectomy along with chemical cauterization (Carnoy’s solution) of the bone after removal of the cyst is recommended.

📖REFERENCES AND FURTHER READING

1. Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4 th ed. Blackwell Munksgaard; 2007.

2. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

3. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

4. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

5. Sapp JP, Eversole LR, Wysocki GP. Contemporary Oral and Maxillofacial Pathology. 2 nd ed. Mosby; 2004.

6. Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch. 2018 Mar;472(3):331-339.

7. MacDonald-Jankowski DS. Orthokeratinized odontogenic cyst: a systematic review. Dentomaxillofacial Radiology. 2010;39(8):455-467.

• Orthokeratinized odontogenic cyst (OOC) was first described as an orthokeratinizing variant of OKC in 1981.

• It is however accepted to be clinico-pathologically different from odontogenic keratocyst (OKC) and is classified as an odontogenic cyst.

• Though there may be similarities between OKC and OOC, there are a few differences that make OOC stand out.

CLINICAL FEATURES

• OOC has a slightly higher male predilection and usually occurs in the third decade.

• Almost 2/3rds (68%) of OOC cases are associated with an unerupted tooth mimicking a dentigerous cyst in the radiograph.

• It affects the mandible more than the maxilla (mand:max-->3:1) and occurs predominantly in the posterior areas.

• OOCs can vary from being small to large lesions. However they are more often associated with swelling of the jaws as compared to OKCs.

• OOC is not clinically aggressive and has a low rate of recurrence.

RADIOLOGY FEATURES

• OOC does not have a characteristic radiographic appearance. It is predominantly (93%) a unilocular lesion.

• Almost 2/3rds of OOC cases show a pericoronal radiolucency (mimics dentigerous cyst).

Remember, pericoronal radiolucency usually refers to a unilocular radiolucency surrounding the crown of the tooth. A pericoronal radiolucency, however can be multilocular (eg – ameloblastoma, unicystic ameloblastoma, CEOT).

HISTOPATHOLOGY FEATURES

• The epithelial lining in OOC is orthokeratinized stratified squamous and has onion-skin like luminal keratinization.

• The epithelial lining has a granular layer with prominent keratohyaline granules and cuboidal to flat basal cells.

• The epithelium- connective tissue interface is flat and has no rete ridges.

TREATMENT

OOC is not an aggressive lesion and is usually treated conservatively by enucleation and curettage.

QUESTIONS? BRING 'EM ON!!

Question 1:

Orthokeratinized odontogenic cyst is a variant of OKC. Is this true?

Answer:

Nope, OOC is not a variant of OKC!

Orthokeratinized odontogenic cyst (OOC) was first described as an orthokeratinizing variant of odontogenic keratocyst (OKC) in 1981. The basis of this distinction was the difference in its histopathology and its reduced chances of recurrence as compared to OKC.

It is now known and accepted that OOC is a distinct clinic-pathologic entityon its own. In factit has been listed as a developmental odontogenic cystin the recent (2017) WHO classification of odontogenic cysts.

Question 2:

Is OOC associated with Gorlin syndrome?

Answer:

Nope, it is not!

One of the distinctions between OOC and OKC is the latter’s association with Gorlin syndrome (Nevoid basal cell carcinoma syndrome). At least 90% of patients with Gorlin syndrome manifest with multiple OKCs. However there have not been records of any association of OOC with Gorlin syndrome.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• OOC is accepted to be clinico-pathologically different from odontogenic keratocyst(OKC) and is classified as an odontogenic cyst. It is not a variant of OKC.

• Almost 2/3rds (68%) of OOC cases are associated with an unerupted tooth mimicking a dentigerous cyst in the radiograph.

• OOC is not clinically aggressive and has a low rate of recurrence.

• The epithelial lining in OOC is orthokeratinized stratified squamous and has onion-skin like luminal keratinization.

• The epithelial lining has a granular layer with prominent keratohyaline granules.

📖REFERENCES AND FURTHER READING

1. MacDonald-Jankowski DS. Orthokeratinized odontogenic cyst: a systematic review. Dentomaxillofacial Radiology. 2010;39(8):455-467.

2. Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch. 2018 Mar;472(3):331-339.

3. Dong Q, Pan S, Sun LS, Li TJ. Orthokeratinized odontogenic cyst: a clinicopathologic study of 61 cases. Arch Pathol Lab Med. 2010 Feb;134(2):271-5.

4. Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4 th ed. Blackwell Munksgaard; 2007.

5. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

6. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

• Dentigerous cyst is the most common “developmental” odontogenic cyst. It makes up 20% of all jaw cysts occurring in the oral cavity.

• This cyst develops as a result of fluid accumulation between the reduced enamel epithelium and the enamel surface of the developing tooth.

• This results in a cyst enclosing the crown and is attached to the cement-enamel junction of the tooth.

Remember that radicular/periapical cyst is the most common odontogenic cyst occurring in the oral cavity (50-60% of all jaw cysts). It however, is an inflammatory cyst (inflammatory in origin; dentigerous cyst is developmental in origin). Dentigerous cyst is the 2nd most common (next to radicular cyst) odontogenic cyst, but most common "developmental" odontogenic cyst.

CLINICAL FEATURES

• Dentigerous cyst predominantly occurs between the second and third decades of life (10-30 years).

• Has a slight male predilection.

• It is associated with an unerupted tooth, usually the mandibular 3^rd molar (65%).

• Most common teeth affected --> mandibular 3^rd molar > maxillary cuspid > maxillary 3^rd molar > mandibular 2^nd premolar.

• Dentigerous cyst may also be rarely associated with a supernumerary tooth or an odontome.

• This cyst is usually asymptomatic and is discovered in radiographs. May also grow to large sizes causing sufficient swelling and facial asymmetry.

RADIOLOGY FEATURES

• Dentigerous cyst shows a pericoronal radiolucency i.e a unilocular radiolucency around the crown of the tooth. The radiolucency usually confines itself upto the CEJ of the tooth.

• There are three radiographic varieties of dentigerous cyst --> a) Central, b) Lateral and c) Circumferential.

  • Central --> Most common variety. Radiolucency surrounds the crown and extends upto CEJ of tooth

  • Lateral -> Radiolucency may extend laterally along the root and partially surround the crown.

  • Circumferential --> Radiolucency extends along the roots and appears to cover the root.

• The diameter of the radiolucency surrounding the crown has to be greater than 3-4 mm or at least 5mm for consideration of a diagnosis of dentigerous cyst. Otherwise, it could be an enlarged follicular space.

( *Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology, quotes 3-4mm to be ideal for diagnosis, while Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology, quotes a space >5mm to be necessary for a diagnosis.)

💡CAUTION!

A suspect diagnosis of a large dentigerous cyst (made with a radiographic examination) could be considered otherwise. Dentigerous cyst is usually small, and large lesions may turn out to be other odontogenic cysts or tumors mimicking dentigerous cyst.

Some lesions mimicking dentigerous cyst in the radiograph (pericoronal radiolucency):  

- Unicystic ameloblastoma
- Conventional ameloblastoma
- Adenomatoid odontogenic tumor
- Odontogenic keratocyst
- Ameloblastic fibroma
- Calcifying epithelial odontogenic tumor (rarely)

HISTOPATHOLOGY FEATURES

• 2-4 layers of flattened non-keratinized odontogenic epithelium lining a loosely fibrous connective tissue.

• The epithelium may be flat or cuboidal and essentially represents the reduced enamel epithelium.

• The connective tissue may harbour small islands or cords of odontogenic epithelium.

💡POTENTIAL COMPLICATIONS

The epithelial lining of dentigerous cyst may potentially undergo a neoplastic transformation and give rise to complications like a) ameloblastoma, b) squamous cell carcinoma and c) mucoepidermoid carcinoma. The possibility of these lesions arising from the dentigerous cyst are however, very rare.

TREATMENT

• Dentigerous cyst is usually treated by enucleation along with removal of involved tooth.

• Large cysts can be treated by marsupialization.

💡ERUPTION CYST: A BRIEF NOTE

• Eruption cyst also called eruption hematoma is the soft tissue variant of dentigerous cyst.

• The pathogenesis of eruption cyst is the same as dentigerous cyst except that the (in the case of eruption cyst) eruption of the associated tooth is impeded in the soft tissue. The cyst comes to surround the tooth in the soft tissue.

• Appears as a blue to purple, small fluctuant and translucent swelling on the alveolar ridge on the site of the erupting tooth.

• Usually seen in children younger than 10 years.

• Teeth most commonly associated with --> deciduous mandibular central incisor > mandibular 1^st permanent molars > deciduous maxillary incisor.

QUESTIONS? BRING ‘EM ON!!

Would dentigerous cyst show its characteristic histopathology picture if it was infected/inflamed?

ANSWER

It wouldn’t! An inflamed dentigerous cyst would show moderate to dense inflammation of the connective tissue. The connective tissue would also become more collagenous/fibrous. Also the epithelium may become hyperplastic, and develop rete ridges.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• Dentigerous cyst is the most common developmental odontogenic cyst.

• This cyst develops as a result of fluid accumulation between the reduced enamel epithelium and the enamel surface of the developing tooth.

• Dentigerous cyst predominantly occurs between the second and third decades of life (10-30 years).

• Most common teeth affected --> mandibular 3^rd molar > maxillary cuspid > maxillary 3^rd molar > mandibular 2^nd premolar.

• There are three radiographic varieties of dentigerous cyst --> a) Central, b) Lateral and c) Circumferential.

• The diameter of the radiolucency surrounding the crown has to be greater than 3-4 mm for consideration of a diagnosis of dentigerous cyst.

• A suspect diagnosis of a large dentigerous cyst (made with a radiographic examination) should be considered otherwise. Dentigerous cyst is usually small, and large lesions may turn out to be other odontogenic cysts or tumors mimicking dentigerous cysts.

• The epithelial lining of dentigerous cyst may potentially undergo a neoplastic transformation and give rise to complications like a) ameloblastoma, b) squamous cell carcinoma and c) mucoepidermoid carcinoma.

• Eruption cyst also called eruption hematoma is the soft tissue variant of dentigerous cyst.

📖REFERENCES AND FURTHER READING

1. Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4 th ed. Blackwell Munksgaard; 2007.

2. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

3. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

4. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

5. Sapp JP, Eversole LR, Wysocki GP. Contemporary Oral and Maxillofacial Pathology. 2 nd ed. Mosby; 2004.

6. Wood NK, Goaz PW. Differential Diagnosis of Oral and Maxillofacial Lesions. 5 th ed. Mosby; 1997.

• Calcifying odontogenic cyst (COC) was first described by Gorlin in 1962.

• It is a cystic lesion characterized histologically by the presence of an ameloblastomatous epithelial lining and ghost cells.

• It is thought to arise from the reduced enamel epithelium or the remnants of dental lamina.

• There has been much confusion as to whether COC could be a cyst, a tumor or a lesion having cystic and tumor variants.

• This lesion was given many different terms --> calcifying cystic odontogenic tumor, calcifying ghost cell odontogenic tumor, dentinogenic ghost cell tumor, calcifying odontogenic lesion and ghost cell cyst.

💡KNOW THY FACTS

- In the 2005 WHO classification, this lesion was termed “Calcifying cystic odontogenic tumor” and was classified as an odontogenic tumor.

- The WHO consensus group in 2017, has reinstated the name “Calcifying odontogenic cyst” and has reclassified the lesion as an odontogenic cyst. The group felt there was sufficient evidence to deem this lesion as a developmental odontogenic cyst. 

- “Dentinogenic ghost cell tumor” is considered to be a distinct entity (not a variant of COC). It is classified as an odontogenic tumor.

CLINICAL FEATURES

• COC is a rare odontogenic cyst and has an equal gender predilection.

• This lesion occurs most commonly in persons in the age groups between 20 – 40 years.

• COC occurs equally in the maxilla and mandible, but favours the anterior region of the jaws (incisor to canine region).

• COC usually presents with a swelling and is mostly asymptomatic.

• COC may rarely present as gingival growths (peripheral lesion) resembling fibromas, usually in the incisor-cuspid region.

RADIOLOGY FEATURES

• COC usually presents as a unilocular radiolucency and is occasionally multilocular.

• Many cases are associated with irregular radiopaque masses within the radiolucencies.

• COCs can be associated with odontomas and at least 1/3^rd of the lesions are associated with unerupted teeth.

• Root resorption and divergence/displacement of teeth is commonly seen.

HISTOPATHOLOGY FEATURES

• The epithelial lining resembles that seen in ameloblastoma. It is a palisaded layer of columnar cells and has an overlying layer of stellate reticulum like cells.

• Ghost cells are seen in the epithelial lining. They are eosinophilic epithelial cells that lack nuclei or cellular organelles. They may become enlarged or ballooned, fuse with each other and form amorphous sheets of eosinophilic material. Ghost cells may undergo calcification.

• There may sometimes be deposits of hyalinised eosinophilic material deposited below the epithelium. This is called dysplastic dentine or dentinoid.

TREATMENT

• COC is usually treated conservatively by surgical enucleation.

QUESTIONS? BRING ‘EM ON!!

1. Is calcifying odontogenic cyst a cyst or a neoplastic cystic tumor?

2. a)What are ghost cells? b)Are they pathognomonic for calcifying odontogenic cyst?

3. How is dysplastic dentin or dentinoid formed?

ANSWERS

1. Refer notes on Tid-Bits - Calcifying Odontogenic Cyst and Ameloblastoma (Note) in the Chapter “Oral Pathology Tid-Bits”.

2. a) Ghost cells are basically eosinophilic epithelial cells that lack nuclei or cellular organelles. In fact these cells may or may not retain their cellular outline, become enlarged or ballooned, fuse with each other and form amorphous sheets of eosinophilic material.

   No one still knows the nature of these cells. While there is a hypothesis that states ghost cells may be a result of abnormal keratinization, there are also theories which propose that these cells may be a phenomenon of coagulative necrosis or abnormal accumulation of enamel proteins. These cells have an affinity for calcification.

   b) Ghost cells are characteristic for COC, and not pathognomonic. Ghost cells can be seen in other lesions such as:

   1. Craniopharyngioma

   2. Pilomatricoma

   3. Dentinogenic ghost cell tumor

   4. Odontoma

   5. Ghost cell odontogenic carcinoma

3. Dysplastic dentin or dentinoid is thought to be dentin like material that arises as a result of an inductive effect of the odontogenic epithelium on the connective tissue cells. This is pretty much like inner enamel epithelium/ameloblasts inducing the dental papilla cells to become odontoblasts, which then secrete dentin.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• COC is a cystic lesion characterized histologically by the presence of an ameloblastomatous epithelial lining and ghost cells.

• The WHO consensus group in 2017, have reinstated the name “Calcifying odontogenic cyst” and have reclassified the lesion as an odontogenic cyst.

• COC occurs frequently in the anterior region of the jaws (incisor to canine region).

• Many cases of COCs are associated with irregular radiopaque masses within the radiolucencies.

• COCs can be associated with odontomas.

• Ghost cells are eosinophilic epithelial cells that lack nuclei or cellular organelles.

• Dysplastic dentin or dentinoid is a hyalinised eosinophilic material deposited below the epithelium.

📖REFERENCES AND FURTHER READING

1. Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch. 2018 Mar;472(3):331-339.

2. Barnes L, Eveson JW, Reichart P, Sidransky D (2005) Odontogenic Tumours. Ch 6, WHO classification of tumors: pathology and genetics of head and neck tumours. IARC, Lyon.

3. Kramer I, Pindborg J, Shear M (1992) WHO International Histological Classification of Tumours. Histological typing of odontogenic tumours, 2nd edn. Springer-Verlag, Berlin.

4. Tomich CE. Calcifying odontogenic cyst and dentinogenic ghost cell tumor. Oral Maxillofac Surg Clin North Am. 2004 Aug;16(3):391-7.

5. Reichart PA, Philipsen HP. Odontogenic tumors and allied lesions. Quintessence Publishing; 2004

6. Shear M, Speight PM. Cysts of the Oral and Maxillofacial Regions. 4 th ed. Blackwell Munksgaard; 2007.

7. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

8. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

9. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

*Table taken from --> Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch. 2018 Mar;472(3):331-339.

💡IMPORTANT CHANGES

• Two lesions previously (2005) classified as odontogenic tumors have been classified as odontogenic cysts.

  1. Keratcystic odontogenic tumor re-designated as “Odontogenic keratocyst” is listed as an Odontogenic cyst

  2. Calcifying cystic odontogenic tumor re-designated as “Calcifying odontogenic cyst” is listed as an Odontogenic cyst

• Orthokeratinized odontogenic cyst is a distinct odontogenic cyst. It is not a variant of Odontogenic keratocyst.

• The classification avoids listing the variants of cysts (though they are odontogenic cysts) like the “Eruption cyst” (variant of Dentigerous cyst) and the “Residual” and “Lateral” cysts (variants/subsets of Radicular cyst).

📖REFERENCES AND FURTHER READING

1. Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch. 2018 Mar;472(3):331-339.

2. Barnes L, Eveson JW, Reichart P, Sidransky D (2005) Odontogenic Tumours. Ch 6, WHO classification of tumors: pathology and genetics of head and neck tumours. IARC, Lyon.

3. Kramer I, Pindborg J, Shear M (1992) WHO International Histological Classification of Tumours. Histological typing of odontogenic tumours, 2nd edn. Springer-Verlag, Berlin.

• Shear and Pindborb in 1980 reported lesions of the oral cavity that were clinically indistinguishable from verrucous carcinoma (VC) but showed slight differences under the microscope.

• They called them “Verrucous Hyperplasia” (VH).

According to them, VH was best distinguished from VC by its broad rete ridges that were in level with the adjacent normal epithelium, not extending deep into the lamina propria.

💡KNOW THY FACTS

There has always been confusion with regards to the diagnosis and terminology of this lesion. And in order to bring some uniformity in reporting this lesion, an expert group of Oral Pathologists held a consensus meeting in Malaysia in 2013. They formulated a set of clinico-pathologic features and proposed the term “Exophytic Verrucous Hyperplasia”.

CLINICAL FEATURES

• EVH clinically, is a solitary white or pink verrucous & exophytic growth greater than 1 cm in size.

• Since its main etiology is betel quid chewing, it could manifest in conjunction with oral submucous fibrosis.

• Apart from these features, EVH has been reported to manifest at a mean age of 54 and predominantly on the buccal mucosa.

• However, care is to be taken while diagnosing this entity, as it resembles verrucous carcinoma and squamous cell carcinoma.

HISTOPATHOLOGY FEATURES

• Histologically, EVH may resemble VC but shows minor differences.

• It shows a hyperkeratotic and a hyperplastic epithelium (usually parakeratosis), with the surface of the lesion having exophytic, verruciform projections.

• There may be depressions or clefts in the epithelium between surface projections, referred to as parakeratin plugs.

• However it mainly differentiates itself from VC in the absence of an endophytic growth of the epithelium. The broad rete ridges are rather in the same level as the adjacent normal epithelium and do not extend deep into the connective tissue unlike VC.

• The other difference is the presence of epithelial dysplasia. But, note that dysplasia may not be always present.

• Certain lesions are also accompanied by a sub-epithelial lymphocytic infiltrate.

TREATMENT AND PROGNOSIS

• As for the prognosis, EVH has shown to manifest with dysplasia and also transform to verrucous carcinoma and squamous cell carcinoma.

• It has in fact been reported to be a distinct entity in the Indian population and some pathologists consider it to be a potentially malignant disorder, though it has not been classified as one by the WHO.

• It is best to treat this lesion like VC and completely excise the lesion.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• There has always been confusion with regards to the diagnosis and terminology of verruscous hyperplasia. And in order to bring some uniformity in reporting this lesion, an expert group of Oral Pathologists held a consensus meeting in Malaysia in 2013. They formulated a set of clinico-pathologic features and proposed the term “Exophytic Verrucous Hyperplasia (EVH)”.

• Since its main etiology is betel quid chewing, it could manifest in conjunction with oral submucous fibrosis.

• Care is to be taken while diagnosing this entity, as it resembles verrucous carcinoma and squamous cell carcinoma.

• EVH mainly differentiates itself from verrucous carcinoma (VC) in the absence of an endophytic growth of the epithelium. The broad rete ridges are rather in the same level as the adjacent normal epithelium and do not extend deep into the connective tissue unlike VC.

📖REFERENCES AND FURTHER READING

1. Shear M, Pindborg JJ. Verrucous hyperplasia of the oral mucosa. Cancer 1980; 46: 1855–62.

2. Zain RB, Kallarakkal TG, Ramanathan A, et al. A consensus report from the first Asian regional meeting on the terminology and criteria for verucco-papillary lesions of the oral cavity held in Kuala Lumpur, Malaysia. Ann Dent Univ Malaya 2013; 20: 1–3.

3. Patil S, Warnakulasuriya S, Raj T, Sanketh DS, Rao RS. Exophytic oral verrucous hyperplasia: a new entity. J Investig Clin Dent. 2016;7(4):417-423.

• Verrucous carcinoma (VC) is a warty, exophytic variant of oral squamous cell carcinoma (OSCC).

• Unlike OSCC, VC rarely exhibits regional or distant metastasis. VC however, is locally invasive and pushes into adjacent or surrounding tissues.

• VC was described in detail by Ackerman in 1948 and is also called Ackerman’s tumor.

• VC is usually associated with a smokeless tobacco/tobacco chewing habit. In fact, VC develops in the site where tobacco was placed and sometimes occurs in conjunction with submucous fibrosis in these patients.

• It may also be associated with patients having smoking or drinking habits, poor oral hygiene, low socio-economic status or rarely no habits at all.

CLINICAL FEATURES

• VC predominantly occurs in elderly males usually in the sixth decade.

• It could potentially occur at any site in the oral cavity. Most common sites --> buccal mucosa, lower alveolar mucosa and vestibule, gingiva and tongue.

• VC clinically appears large & diffuse, verrucous, warty or exophtic with distinct borders.

• The lesion may be white or sometimes red-white in colour.

• VC has a low propensity for metastasis but is locally invasive. If left untreated it could push and invade adjacent structures like periosteum, bone and salivary glands.

• Enlarged lymph nodes in individuals with VC are due to secondary inflammatory changes and are not due to metastatis of the lesion.

• VC could occur in conjunction with other oral potentially malignant disorders like leukoplakia and oral submucous fibrosis.

💡KNOW THY FACTS

Exophytic verrucous hyperplasia (EVH) is a verrucous lesion, known to occur in association with betel quid chewing that clinically and histopathologically resembles VC. However, EVH is distinguished histopathologically from VC by the absence of an endophytic growth pattern. Also, EVH though not always, may manifest with epithelial dysplasia.

HISTOPATHOLOGY FEATURES

• The epithelium has a verruciform or exophytic surface with clefts in between the exophtic projections.

• The clefts are filled with parakeratin --> parakeratin plugging.

• The epithelium is hyperplastic and is deceptively benign. It does not show dysplastic features (rarely manifests dysplasia).

• Rete ridges are elongated, thick and bulky, and push into the adjacent connective tissue. The rete ridges are described as having an “elephant’s foot” appearance.

• The characteristic feature of verrucous carcinoma is its endophytic growth pattern --> the lesional epithelium, with an intact basement membrane, pushes deep into the connective tissue (but does not invade the connective tissue like squamous cell carcinoma) and grows beyond the level of the basement membrane of the adjacent normal epithelium.

• VC may show a dense inflammatory infiltrate in the connective tissue immediately below the epithelium.

💡CAUTION

- An adequate incisional biopsy is required for an accurate diagnosis of VC. Some amount of normal tissue is to be incised along with the lesional tissue. This is because normal epithelium is required for a comparison with the lesional tissue in order to establish the endophytic growth of VC (refer histopathology features). 

- Also care must be taken to rule out any foci of squamous cell carcinoma (foci of lesional epithelium in the connective tissue) in the VC specimen.

TREATMENT

• A complete surgical excision is the treatment of choice.

• VC has an excellent prognosis with surgical management.

• Patients are to be kept under follow-up as there are chances of recurrence of the lesion. Recurrence for VC has been reported in the range of 6-40% of the cases.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• Unlike OSCC, VC rarely exhibits regional or distant metastasis. VC however, is locally invasive and pushes into adjacent or surrounding tissues.

• Enlarged lymph nodes in individuals with VC are due to secondary inflammatory changes and are not due to metastatis of the lesion.

• VC could occur in conjunction with other oral potentially malignant disorders like leukoplakia and oral submucous fibrosis

• The epithelium is hyperplastic and is deceptively benign. It does not show dysplastic features (rarely manifests dysplasia).

• Rete ridges are elongated, thick and bulky, and push into the adjacent connective tissue. The rete ridges are described as having an “elephant’s foot” appearance.

• The characteristic feature of verrucous carcinoma is its endophytic growth pattern.

REFERENCES AND FURTHER READING

1. Donald PM, Renjith G, Arora A. Tobacco Pouch Keratosis in a young individual: A brief description. J Indian Soc Periodontol. 2017;21(3):249–251.

2. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

3. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

4. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

• Tobacco pouch keratosis (TPK) is also synonymously called snuff dipper’s lesion and smokeless tobacco keratosis.

• TPK, as the name implies is a white keratotic lesion that appears in the mucosa due to a chronic smokeless tobacco habit. The affected mucosa is pouch-like because it becomes soft, wrinkled and flaccid on chronic contact with tobacco.

• TPK is not a potentially malignant disorder and does not show dysplasia histopathologically.

• Long term usage of smokeless tobacco may however induce lesions like leukoplakia (showing dysplasia or carcinoma) and verrucous carcinoma.

ETIOLOGY

• TPK is induced by chronic usage of smokeless tobacco.

• Smokeless tobacco habit is prevalent among people in United States, Sweden, India and other South-East Asian countries.

• Smokeless tobacco is known to have carcinogens like nitrosonornicotine.

• Also its high alkalinity (8.2-9.3) along with its constant contact with the mucosa induces inflammation and a keratotic response.

💡KNOW THY FACTS!

Smokeless tobacco is available in different forms --> a) dry snuff, b) moist snuff & c) chewing tobacco. While people in the western part of the world usually use snuff, people in India and South-Asian countries mostly use chewing tobacco along with betel leaves, arecanut, lime and other spices. However, it is shredded tobacco (snuff) which has more potential to cause these lesions.

CLINICAL FEATURES

• TPK is prevalent among the young (adolescents/teenagers) and the older (6^th decade) age group, predominantly men although certain subpopulations have older women more commonly affected.

• The lesion appears in the mucosa that is directly in contact with tobacco. It is habitually placed in the mandibular vestibular area (buccal or labial).

• The mucosa in individuals with TPK initially appears soft, wrinkled and granular. TPK does not have distinct borders.

• The mucosa progresses to become a leathery and keratotic (white or grey coloured) with heavy folding of the mucosa.

• TPK has been described as having an appearance resembling “sand on a beach after an ebbing tide”.

• Pouching tobacco in the oral mucosa has also been associated with gingival recession (that gingiva in contact with tobacco).

HISTOPATHOLOGY FEATURES

• Histopathology is non-specific.

• Affected mucosa shows an epithelium with hyperkeratosis and acanthosis (hyperplasia of the spinous layer).

• The corneal layer may sometimes have pointed projections of keratin called “chevrons”.

• The upper layers of the epithelium may show intracellular edema or “vacuolization”.

• The connective tissue shows sparse inflammatory infiltrate.

• TPK does not show epithelial dysplasia.

TREATMENT

No treatment is required as these lesions regress in a few weeks on cessation of the habit (smokeless tobacco).

CAUTION!

TPK is a white keratotic and wrinkled lesion that resembles leukoplakia. It is important to distinguish this lesion from leukoplakia, as it usually disappears on cessation of the habit; and also does not show dysplasia histopathologically. However, if the lesion persists for at least 4-6 weeks even on cessation of the habit, the lesion could well be leukoplakia. It would be wise to take a biopsy to check for dysplastic or malignant changes.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• Tobacco pouch keratosis (TPK) is also synonymously called snuff dipper’s lesion and smokeless tobacco keratosis.

• TPK is not a potentially malignant disorder and does not show dysplasia histopathologically.

• The lesion appears in the mucosa that is directly in contact with tobacco. It is habitually placed in the mandibular vestibular area (buccal or labial).

• TPK has been described as having an appearance resembling “sand on a beach after an ebbing tide”.

• TPK does not show epithelial dysplasia.

• If TPK persists for at least 4-6 weeks even on cessation of the habit (smokeless tobacco), the lesion could well be leukoplakia. It would be wise to take a biopsy to check for dysplastic or malignant changes.

📖REFERENCES AND FURTHER READING

1. Donald PM, Renjith G, Arora A. Tobacco Pouch Keratosis in a young individual: A brief description. J Indian Soc Periodontol. 2017;21(3):249–251.

2. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

3. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

4. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

• Oral submucous fibrosis (OSF) is a chronic debilitating and scarring disease of the oral mucosa that is potentially malignant.

• It is a condition characterized by an altered collagen metabolism which results in dense fibrosis of the oral cavity.

• OSF was first described by Schwartz in 1952, and was then termed “atrophica idiopathica mucosae oris”. It was later renamed as OSF by Joshi 1953.

• OSF is rare in the western countries and is most prevalent in India and South-East Asia.

ETIOLOGY & PATHOGENESIS

• The main etiology for OSF is known to be betel quid chewing.

• The dense fibrosis caused in this condition is due to the presence of arecanut in betel quid.

💡KNOW THY FACTS!

Betel quid consists of a betel leaf that wraps a mixture of arecanut, slaked lime (calcium hydroxide), tobacco and other spices. Other freeze-dried betel quid substitutes are pan masala, gutkha and mawa. The main constituent known to induce OSF is the arecanut present in betel quid and its substitutes.

• There has been sufficient research hypothesizing arecoline, an alkaloid of arecanut, to cause a disruption in the collagen metabolism that potentially leads to OSF.

INCREASED PRODUCTION OF COLLAGEN

• Arecoline induces inflammatory cells to produce cytokines --> IL-1, IL-6, IL-8 and TNF-α. These cytokines can cause fibroblasts to increase collagen production.

• Arecoline could upregulate the production of growth factors --> PDGF, TGF-β and FGF, which cause fibroblast to increase collagen production.

DECREASED DEGRADATION OF COLLAGEN

• Arecoline could cause a reduction in phagocytic removal of collagen. This could cause decreased degradation of collagen.

• Tannins (polyphenol) and copper in arecanut cause an increase in enzyme, lysyl oxidase --> causes abnormal cross-linking of collagen molecules --> decreased degradation of collagen.

• Matrix metalloproteinase (MMP) degrades collagen; Tissue inhibitors of matrix metalloproteinases (TIMP) inhibit action of MMPs. Arecoline disturbs the balance between MMPs & TIMPs tipping it in the favour of TIMP. Increase in TIMP --> inhibition of MMP --> decreased collagen degradation.

OTHER FACTORS

• Nutritional deficiencies like iron and vitamin B complex deficiency, as well as malnutrition could be promoting factors of the disease.

• Genetic and molecular alterations have also been reported to contribute to pathogenesis of the disease.

CLINICAL FEATURES

• Prevalent in India and South-East Asia usually in individuals between 40-60 years.

• There has been an increase in the younger population affected by this disease (could be due to increase in adverse habits among the young).

• A general female predilection has been reported though certain reports show a male predominance.

• Early symptoms of OSF include a) burning sensation of the mouth (stomatopyrosis), b) appearance of blisters, ulcerations in the oral cavity and c) dryness of mouth.

• OSF progresses to increased fibrosis --> blanching of oral mucosa.

• Blanching starts from the lips or buccal mucosa and proceeds backwards.

• Fibrous bands can be palpated (in tissues affected), usually running vertically.

• Fibrosis spreads to the pterygomandibular raphae --> decreased mouth opening – trismus.

• Advanced cases of OSF may have mouth opening reduced to <15mm (normal mouth opening – 39-70 mm for male; 36-56mm for female).

• Fibrosis could also spread to the soft palate (causes deviation of uvula) and up to the pharynx.

• OSF patients find it difficult to open their mouth, eat, swallow and whistle/blow.

💡KNOW THY FACTS!

- Betel quid chewing, apart from causing OSF is also known to cause other potentially malignant disorders like leukoplakia, verrucous hyperplasia and verrucous carcinoma. This is primarily due to the tobacco present in the betel quid, although it is also reported that arecoline can induce carcinogenesis.

- Another interesting lesion caused due to betel quid chewing is the oral lichenoid lesion appearing in tissues directly in contact with the betel quid.These lesions may present as fine white wavy, parallel striae and may sometimes radiate from a central erythematous area.

MALIGNANT POTENTIAL OF OSF

• OSF is classified as a potentially malignant disorder and is estimated to have a 7-13% rate of malignant transformation to oral squamous cell carcinoma (OSCC).

• a) Dense fibrosis, b) lack of vascularity c) altered cytokines in the tissues of patients with OSF provides for a unique environment conducive for tobacco and arecanut to induce carcinogenesis.

HISTOPATHOLOGY FEATURES

EARLY STAGE

• Epithelium shows flattening of rete ridges.

• Juxta-epithelial hyalinization --> glassy, homogenous eosinophilic material deposited in connective tissue immediately below epithelium.

• Presence of moderate numbers of plump fibroblasts.

• Dilated and congested blood vessels in connective tissue.

• Sparse inflammation usually lymphocytes and occasional plasma cells.

MODERATELY ADVANCED STAGE

• Epithelium loses rete ridges, is markedly atrophic.

• Moderately hyalinized collagen in connective tissue (due to increasing fibrosis).

• Blood vessels begin to constrict.

• Inflammatory infiltrate consists of lymphocytes, plasma cells and few eosinophils.

ADVANCED STAGE

• Connective tissue densely fibrosed and hyalinized (appears as a smooth sheet).

• Connective tissue devoid of fibroblast.

• Blood vessels are obliterated.

• Inflammatory infiltrate consists of lymphocytes, plasma cells and few eosinophils.

OTHER CHANGES

• Epithelial dysplasia without carcinoma is found in 10-15% of cases.

• OSCC is found in 5 % of cases submitted for biopsy.

TREATMENT

• Intralesional injections or topical application of corticosteroids.

• Hyaluronidase either topically or in combination with steroid injections are shown to improve symptoms faster and have better long term results.

• Nutritional supplements like multivitamins and antioxidants improve symptoms.

• Surgical excision of the fibrotic bands and laser fibrotomy could be useful in managing oral submucous fibrosis.

✅HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• OSF is a condition characterized by an altered collagen metabolism which results in dense fibrosis of the oral cavity.

• The dense fibrosis caused in this condition is due to the presence of arecanut in betel quid.

• Arecoline could upregulate the production of growth factors which cause fibroblast to increase collagen production.

• Tannins (polyphenol) and copper in arecanut cause an increase in enzyme, lysyl oxidase --> causes abnormal cross-linking of collagen molecules --> decreased degradation of collagen.

• Blanching starts from the lips or buccal mucosa and proceeds backwards.

• Fibrous bands can be palpated (in tissues affected), usually running vertically.

• OSF is classified as a potentially malignant disorder and is estimated to have a 7-13% rate of malignant transformation to oral squamous cell carcinoma (OSCC).

• Early stage OSF - Juxta-epithelial hyalinization --> glassy, homogenous eosinophilic material deposited in connective tissue immediately below epithelium.

• Advanced stage OSF - Connective tissue densely fibrosed and hyalinized (appears as a smooth sheet).

• Hyaluronidase either topically or in combination with steroid injections are shown to improve symptoms faster and have better long term results.

QUESTIONS? BRING 'EM ON!!

1. As OSF progresses, it is noted (under the microscope) that the blood vessels begin to constrict and are obliterated in advanced stages. a) Why does this happen? b) Does this have any effect?

2. OSF can regress and oral mucosa could return to normalcy on quitting adverse habits – betel quid/arecanut chewing. Is this true?

ANSWERS

1. a) Progressive fibrosis of the connective tissue in OSF could cause obliteration of blood vessels and reduction in vascularity. Also there are studies reporting arecoline to possibly have cytotoxic effects on endothelial cells leading to impairment of vascular function.

   b) The hypoxic environment due to reduced vascularity is one of the many reasons OSF can progress to malignancy.

2. No, OSF unfortunately is irreversible, and reduction or stopping the habit completely can at best slow the progress of the disease (if detected in early stages). Quitting the adverse habit is an important preventive measure. Treatment for OSF is symptomatic.

📖REFERENCES AND FURTHER READING

1. Ekanayaka RP, Tilakaratne WM (2013) Oral Submucous Fibrosis: Review on Mechanisms of Pathogenesis and Malignant Transformation.J Carcinogene Mutagene S5: 002.

2. Wollina U, Verma SB, Ali FM, Patil K. Oral submucous fibrosis: an update. Clin Cosmet Investig Dermatol. 2015;8:193–20.

3. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

4. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

5. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

6. Lountzis NI, Ferringer T, Macaron N, Howard A. Oral Submucous Fibrosis. 2016. Available at https://emedicine.medscape.com/article/1077241-overview

• Oral squamous cell carcinoma (OSCC), very simply put, is a malignant neoplasm of the squamous cell or keratinocyte.

• Various factors induce DNA mutations in the squamous cell, causing excess proliferation of these cells leading to cancer.

• OSCC is known to be the most common oral malignancy. It is reported to account for 90% of all cancers occurring in oral cavity.

• Very often, OSCC is preceded by oral potentially malignant disorders like leukoplakia or erythroplakia.

ETIOLOGY

OSCC is known to have a multifactorial etiology. There are many factors that could possibly lead to causing OSCC.

Tobacco (smoking and smokeless)

• Both tobacco smoking and smokeless tobacco are regarded to be strongly linked to cause OSCC. In fact, majority of individuals with OSCC are known to have a smoking habit.

• Pipe and cigar smoking are reported to be riskier than cigarette smoking when it comes to causing OSCC. Pipe smokers have a strong predilection for squamous cell carcinoma of the lower lip.

• Bidi smoking, prevalent in places like India, is known to be 3 times riskier than cigarette smoking.

• A deleterious habit called “Reverse smoking”, where the smoker keeps the lighted end of the cigarette inside the mouth, is known to have the highest risk of causing OSCC. In these cases, it is the hard palate that is usually affected.

• Other habits like chewing dry/wet snuff and tobacco pouching are also known to cause OSCC.

💡KNOW THY FACTS

Tobacco smoking or chewing, is the most common etiologic factor in causing OSCC in places like India. Most commonly, tobacco habits lead to causing oral potentially malignant disorders like leukoplakia, erthroplakia, leuko-erythroplakia and submucous fibrosis. Though not all of them transform, they have the potential to become malignant. Most cases of OSCC are preceded by dysplastic potentially malignant disorders.

Alcohol

• Though it does not have a direct correlation, alcohol is reported to work in synergy with tobacco in causing OSCC.

• Alcohol in combination with tobacco is a considerable risk factor.

Betel quid

• Betel quid consists of a betel leaf that wraps a mixture of arecanut, slaked lime (calcium hydroxide), tobacco and other spices.

• Betel quid chewing is mainly implicated in causing oral submucous fibrosis (OSF). However, it is also reported that, arecoline (an alkaloid of arecanut) can induce carcinogenesis.

• Moreover, OSF is classified as a potentially malignant disorder and is estimated to have a 7-13% rate of malignant transformation to OSCC.

Nutritional deficiencies

• High fat and sugar intake, with low fruits and vegetable intake has been implicated to be a risk factor.

• Low levels of Vitamin A and C.

• Plummer-Vinson syndrome (also called Paterson-Kelly syndrome) is one of the most significant manifestations of iron deficiency anemia. It predisposes an individual to pharyngeal or esophageal squamous cell carcinoma.

Immunosuppression

• Patients with a compromised immune system have considerable risk in developing OSCC.

• HIV/AIDS patients --> increased risk of oral cancer.

• Patients whose immune systems are suppressed for bone marrow or organ transplant (kidney) have been reported to develop oral cancer.

HPV and Candida

• A number of studies have reported Human Papilloma Virus (HPV) to be associated with oro-pharyngeal carcinomas.

• Certain strains of Candida albicans are known to produce N-nitrosobenzylmethylamine, which is a carcinogen. It has been reported that these products either directly or in association with other carcinogens could induce OSCC.

• A clinical type of candidal lesion called Hyperplastic candidiasis (previously called chonic hyperplastic candidiasis) is known to manifest with dysplasia histologically.

💡KNOW THY FACTS

There are reports that state candida organisms could induce hyperplasia and cause hyperkeratotic white lesions. Hence, some pathologists and investigators believe hyperplastic candidiasis could cause dysplastic leukoplakic lesions and regard them as being potentially malignant. 

However, there are researchers who doubt this condition could arise as a result of candida and believe it to be a “candidal infection superimposed on a pre-existing leukoplakic lesion”.

PATHOGENESIS

• The above listed etiologic factors or mutagens (especially tobacco and betel quid) could cause genetic alterations/mutations of the squamous cell, that alter their biologic behavior.

• Accumulated/induced mutations help the damaged cells to persist (escape apoptosis) and proliferate (read more on this in the lesson “Oral Epithelial Dysplasia“).

• At this stage mutated squamous cells are tumor cells and are histologically atypical (dysplastic).

• Usually there is a healthy balance of cell proliferation (induced by oncogenes) and cell cycle arrest (by tumor suppressor genes). Mutations accumulating in oncogenes and tumor suppressor genes result in altered cell behavior and carcinogenesis.

Oncogenes

• Oncogenes are proteins that help cells proliferate.

• Mutations in oncogenes could cause uncontrolled proliferation of cells.

Tumor suppressor genes

• Tumor suppressor genes are proteins that help arrest the cell cycle (proliferation) and also cause apoptosis of the cell when necessary.

• Mutations in tumor suppressor genes (usually p16, p53 and p21) could cause uncontrolled proliferation of cells (since mutations cause the tumor suppressor genes from functioning properly, thus indirectly helping proliferation).

HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• OSCC is known to be the most common oral malignancy. It is reported to account for 90% of all cancers occurring in oral cavity.

• Pipe smokers have a strong predilection for squamous cell carcinoma of the lower lip.

• A deleterious habit called “Reverse smoking”, where the smoker keeps the lighted end of the cigarette inside the mouth, is known to have the highest risk of causing OSCC.

• Alcohol in combination with tobacco is a considerable risk factor.

• Betel quid chewing is mainly implicated in causing oral submucous fibrosis (OSF). However, it is also reported that, arecoline (an alkaloid of arecanut) can induce carcinogenesis.

• Plummer-Vinson syndrome (also called Paterson-Kelly syndrome) is one of the most significant manifestations of iron deficiency anemia. It predisposes an individual to pharyngeal or esophageal squamous cell carcinoma.

• A number of studies have reported Human Papilloma Virus (HPV) to be associated with oro-pharyngeal carcinomas.

• Certain strains of Candida albicans are known to produce N-nitrosobenzylmethylamine, which is a carcinogen. It has been reported that these products either directly or in association with other carcinogens could induce OSCC.

• Usually there is a healthy balance of cell proliferation (induced by oncogenes) and cell cycle arrest (by tumor suppressor genes). Mutations accumulating in oncogenes and tumor suppressor genes result in altered cell behavior and carcinogenesis.

QUESTIONS? BRING 'EM ON!!

Note: Reading the next part of this lesson (Oral squamous cell carcinoma - Clinical features and Histopathology could help you answer this question)

Q: A 63 year old male was clinically diagnosed with verrucous leukoplakia. A biopsy was done and the histopathology report was as follows:

“The H & E stained section shows hyperkeratotic parakeratinized hyperplastic stratified squamous epithelium with exophytic projections, overlying a densely inflamed stroma. The epithelium shows clefts with keratin plugging in several areas and broad bulbous rete ridges with an endophytic growth pattern. The connective tissue shows dense inflammation with focal areas of nests and islands of dysplastic epithelial cells.”

What would be the most likely diagnosis (refer the histopathology section for clues)??

ANSWER

The lesion should be diagnosed as squamous cell carcinoma!

The biopsy report revealed the lesion had all features diagnostic of verrucous carcinoma. Diagnosis of verrucous carcinoma is confirmed, when the broad rete ridges show an endophytic growth, i.e, the lesional rete ridges “push” into the connective tissue with an intact basement membrane, beyond the adjacent basement membrane of the normal epithelium.

However, note the last line of the report which says “The connective tissue shows focal areas of nests and islands of dysplastic epithelial cells”. Verrucous carcinoma does not show invasion of epithelial cells into the connective tissue unlike squamous cell carcinoma. In fact, it is important for pathologists to screen the lesion thoroughly, to check for foci of conventional squamous cell carcinomas within a verrucous carcinoma. Foci of invading dysplastic epithelial islands in the connective tissue should raise a “red flag” and such lesions should be diagnosed and treated as conventional squamous cell carcinomas.

REFERENCES AND FURTHER READING

1. Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol. 2009;45(4-5):301-308.

2. Pires FR, Ramos AB, Oliveira JB, Tavares AS, Luz PS, Santos TC. Oral squamous cell carcinoma: clinicopathological features from 346 cases from a single oral pathology service during an 8-year period. J Appl Oral Sci. 2013;21(5):460-467.

3. Sanketh DS, Patil S, Rao RS. Estimating the frequency of Candida in oral squamous cell carcinoma using Calcofluor White fluorescent stain. J Investig Clin Dent. 2016;7(3):304-307.

4. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

5. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

6. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

7. Sapp JP, Eversole LR, Wysocki GP. Contemporary Oral and Maxillofacial Pathology. 2 nd ed. Mosby; 2004.

CLINICAL FEATURES

• OSCC is reported to occur more commonly in older males (higher male predilection) in the lower socio-economic groups.

• Though OSCCs could arise in a normal mucosa, most often they are preceded by potentially malignant disorders like leukoplakia, erythroplakia or mixed red-white lesions like speckled leukoplakia/leukoerythroplakia.

CLINICAL MANIFESTATIONS

• OSCCs appear either as ulcerative lesions or exophytic lesions.

• Ulcerative lesions may have rolled out borders or raised/exophytic margins.

• Exophytic lesions (may be ulcerated too) appear verruciform or papillary.

Other clinical manifestations suggestive of OSCC
- red lesions suggestive of erythroplakia
- white lesions suggestive of leukoplakia
- mixed red-white lesions 
- multifocal white or white-red lesions suggestive of proliferative verrucous leukoplakia
- lump on the oral mucosa
- a non healing extraction socket

• OSCC could appear in any site in the oral mucosa -> buccal mucosa, gingiva, tongue, floor of the mouth, lips and hard palate.

• Buccal mucosa and gingiva -> OSCC occurs on this site usually in individuals with tobacco chewing habits. These individuals have a habit of pouching snuff in the gingivo-buccal sulcus leading to the lesion appearing in the associated buccal mucosa and gingiva.

• Tongue -> the posterior lateral tongue and posterior one third of the tongue are usually affected. There is regional lymph node metastasis by the time the lesion is diagnosed. Prognosis is bad.

• Floor of the mouth -> like the tongue, the prognosis for individuals with OSCC in this site is poor.

• Lips -> lower lips are affected more frequently than the upper lip. The prognosis for OSCC on the lower lip is very good as compared to the upper lip which is worse.

• Hard Palate -> very rare for OSCC to appear in this site. Individuals with the reverse smoking habit have their hard palate affected.

HISTOPATHOLOGY FEATURES

• OSCC lesions are those in which the dysplastic epithelium has breached the basement membrane and invaded the connective tissue.

• Strictly speaking even if a single cell breaches the basement membrane and invades the connective tissue, that lesion is considered to be carcinomatous.

• Under the microscope, the lesional tissue is dysplastic (read “epithelial dysplasia“) and shows cords, nests, islands or sheets of dysplastic squamous epithelium in the connective tissue.

• The invading cords, nests or islands of malignant epithelial cells would extend deeply, penetrate and destroy other connective tissue components like adipose tissue, muscle, blood vessels or bone.

• A characteristic feature of OSCC is the formation of keratin pearls and presence of individual cell keratinization.

Atypical epithelial cells may abnormally produce keratin within a single cell which is referred to as dyskeratosis. Numerous abnormal cells may produce abnormal keratin which accumulates in focal areas as pools of keratin. These foci of abnormal keratin are called keratin pearls.

• The connective tissue could show dense inflammation.

• OSCC is graded as well, moderately and poorly differentiated based on its histologic resemblance to squamous epithelium.

• Well-differentiated OSCC is easy to diagnose, very closely resembles squamous epithelium (tissue of origin). It usually shows numerous keratin pearls histologically. Squamous cells/keratinocytes produce keratin. Numerous abnormal cells (keratinocytes) may produce abnormal keratin which accumulates in focal areas as pools of keratin.

• Cells in a poorly differentiated OSCC lesion would show marked pleomorphism to the extent of becoming anaplastic. They are very immature, show no keratinization or keratin pearls, and do not bear any resemblance to their tissue of origin. Such cases may need immunohistochemistry stains to identify the tissue of origin in order to diagnose the lesion.

• Moderately differentiated OSCC lesions stand somewhere in between and show considerable pleomorphism, while also showing a few keratin pearls and some resemblance to the tissue of origin.

• Among the 3 histologic grades, a well differentiated lesion has the best prognosis and a poorly differentiated tumor has the worst prognosis.

KNOW THY FACTS

• Only when the epithelial cells have invaded the connective tissue is the lesion branded a “carcinoma”. A dysplastic epithelium without invasion is termed “epithelial dysplasia”.

• An exception to this rule is “Verrucous carcinoma” where there is no connective tissue invasion by the epithelium.

A BRIEF NOTE ON TNM STAGING

• OSCC is staged based on 3 parameters, in order to predict the prognosis of the lesion.

• The 3 parameters taken into account are:

  1. Tumor size

  2. Regional Lymph Node involvement

  3. Distant Metastasis

• These parameters are determined and are used for staging the tumor (OSCC lesion).

• OSCC, based on the TNM staging, can be worked into 5 stages -> stage 0, through stage IV. The higher the stage of the tumor, the worse is its prognosis.

TREATMENT

• OSCC, based on its size and site, is treated by surgical excision, radiation therapy or both.

• Also based on regional lymph node involvement, it is treated with a combination of lymph node dissection.

• Treatment and prognosis of OSCC depends on the site of the lesion, staging as well as the histologic grade.

HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• OSCC is known to be the most common oral malignancy. It is reported to account for 90% of all cancers occurring in oral cavity.

• OSCC occurs on buccal mucosa and gingiva in individuals with tobacco chewing habits. These individuals have a habit of pouching snuff in the gingivo-buccal sulcus leading to the lesion appearing in the associated buccal mucosa and gingiva.

• OSCC lesions are those in which the dysplastic epithelium has breached the basement membrane and invaded the connective tissue.

• Under the microscope, the lesional tissue is dysplastic (read “epithelial dysplasia“) and shows cords, nests, islands or sheets of dysplastic squamous epithelium in the connective tissue.

• A characteristic feature of OSCC is the formation of keratin pearls and presence of individual cell keratinization.

• OSCC is graded as well, moderately and poorly differentiated based on its histologic resemblance to squamous epithelium.

• Among the 3 histologic grades, a well differentiated lesion has the best prognosis and a poorly differentiated tumor has the worst prognosis.

QUESTIONS? BRING ‘EM ON!!

Q: A 63 year old male was clinically diagnosed with verrucous leukoplakia. A biopsy was done and the histopathology report was as follows:

“The H & E stained section shows hyperkeratotic parakeratinized hyperplastic stratified squamous epithelium with exophytic projections, overlying a densely inflamed stroma. The epithelium shows clefts with keratin plugging in several areas and broad bulbous rete ridges with an endophytic growth pattern. The connective tissue shows dense inflammation with focal areas of nests and islands of dysplastic epithelial cells.”

What would be the most likely diagnosis (refer the histopathology section for clues)??

ANSWER

The lesion should be diagnosed as squamous cell carcinoma!

The biopsy report revealed the lesion had all features diagnostic of verrucous carcinoma. Diagnosis of verrucous carcinoma is confirmed, when the broad rete ridges show an endophytic growth, i.e, the lesional rete ridges “push” into the connective tissue with an intact basement membrane, beyond the adjacent basement membrane of the normal epithelium.

However, note the last line of the report which says “The connective tissue shows focal areas of nests and islands of dysplastic epithelial cells”. Verrucous carcinoma does not show invasion of epithelial cells into the connective tissue unlike squamous cell carcinoma. In fact, it is important for pathologists to screen the lesion thoroughly, to check for foci of conventional squamous cell carcinomas within a verrucous carcinoma. Foci of invading dysplastic epithelial islands in the connective tissue should raise a “red flag” and such lesions should be diagnosed and treated as conventional squamous cell carcinomas.

REFERENCES AND FURTHER READING

1. Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol. 2009;45(4-5):301-308.

2. Pires FR, Ramos AB, Oliveira JB, Tavares AS, Luz PS, Santos TC. Oral squamous cell carcinoma: clinicopathological features from 346 cases from a single oral pathology service during an 8-year period. J Appl Oral Sci. 2013;21(5):460-467.

3. Sanketh DS, Patil S, Rao RS. Estimating the frequency of Candida in oral squamous cell carcinoma using Calcofluor White fluorescent stain. J Investig Clin Dent. 2016;7(3):304-307.

4. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

5. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

6. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

7. Sapp JP, Eversole LR, Wysocki GP. Contemporary Oral and Maxillofacial Pathology. 2 nd ed. Mosby; 2004.

ETIOLOGY & PATHOGENESIS

• NS is associated with long term tobacco smoking.

• Though called “nicotine” stomatitis, the lesion is not due to the chemical content of the nicotine itself. It is rather, due to the heat generated by the tobacco product.

• The heat may act as a local irritant, leading to a reactionary hyperplasia and keratosis of the palatal epithelium, and inflammation of the minor salivary gland ducts of the palate.

• Hence, the palate of a denture wearer (who chronically smoke) is protected from developing this lesion.

💡REVERSE SMOKING

• There is a form of smoking called “reverse smoking” that has been reported in various populations in Philippines, The Caribbean, Columbia and India.

• The tobacco product is reverse smoked with the lit end/burning end of the cigarette inside of the oral cavity.

• The changes on the palate caused as a result is collectively termed “Palatal lesions/changes due to reverse smoking” (because there could be a variety of changes apart from just keratosis) and should not be confused with nicotine stomatitis.

• Palatal lesions/changes due to reverse smoking are potentially malignant with a high rate of malignant transformation.

DID YOU KNOW?

- In India, reverse smoking is quite prevalent among fishermen of coastal rural Andhra Pradesh.
- In the local language this habit is called "Adda Poga".
- The tobacco product is made by rolling dried tobacco twigs and is called "chutta".

Reference:
Bharath TS, Kumar NG, Nagaraja A, Saraswathi TR, Babu GS, Raju PR. Palatal changes of reverse smokers in a rural coastal Andhra population  with review of literature. J Oral Maxillofac Pathol. 2015;19(2):182-187.

CLINICAL FEATURES

• NS is commonly found in men, probably because the habit is more prevalent among men.

• NS can appear at any age, though it is commonly reported in the older age group, usually 45 years and up.

• The lesion is confined to the mucosa of the hard palate, usually the posterior region.

• NS is a diffuse white, keratotic lesion with numerous raised papules that have red punctate centres.

• The lesion is usually fissured or wrinkled.

• The raised papules with red centres represent inflamed minor salivary gland ducts.

• The lesion starts of as diffuse erythema and progresses to become white, thickened, fissured and wrinkled.

• Patients are asymptomatic and are not aware of the lesion until later.

💡 PALATAL CHANGES THAT OCCUR DUE TO REVERSE SMOKING

Reverse smoker’s palate unlike nicotine stomatitis, can manifest with a variety of appearances.

• Keratosis

• Raised white patches

• Diffuse red areas

• Ulcerated areas

• Areas of hyperpigmentation and depigmentation

HISTOPATHOLOGY FEATURES

• The lesion, under the microscope, shows hyperkeratosis and acanthosis of the epithelium.

• The connective tissue and the areas around minor salivary gland ducts may show mild to moderate inflammation.

• In addition, there may be squamous metaplasia of the salivary gland ductal epithelium.

• The epithelium does not show epithelial dysplasia.

REMEMBER...

- Nicotine stomatitis (NS) arises as a result of the heat generated by the tobacco product and is not due to the tobacco itself.
- Therefore NS, though arising in chronic smokers, is not a potentially malignant disorder.
- In fact, the epithelium does not show dysplastic changes.

TREATMENT

• The lesion is completely reversible and resolves on cessation of smoking.

• The lesion should generally resolve within a week or two (if smoking is stopped).

CAUTION

• If the lesion persists for more than 4 weeks even after cessation of the smoking habit, the clinician may have to exercise caution. Such lesions (which do not regress/resolve) may well be leukoplakias, and may deserve further scrutiny to check for dysplastic changes.

• Though NS is not potentially malignant, it is a marker for heavy, long term tobacco smoking. In such patients, it is better to check for any suspect premalignant lesions elsewhere in the oral cavity.
  

HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• Nicotine stomatitis (NS) or “smoker’s palate” is a form of keratosis occurring on the hard palate due to long term smoking.

• It is very commonly seen in pipe smokers. However, it is also present in patients with cigarette and cigar smoking, though, less commonly.

• Though called “nicotine” stomatitis, the lesion is not due to the chemical content of the nicotine itself. It is rather, due to the heat generated by the tobacco product.

• The heat may act as a local irritant, leading to a reactionary hyperplasia and keratosis of the palatal epithelium, and inflammation of the minor salivary gland ducts of the palate.

• In reverse smoking, the tobacco product is reverse smoked with the lit end/burning end of the cigarette inside of the oral cavity.

• Palatal lesions/changes due to reverse smoking are potentially malignant with a high rate of malignant transformation.

• NS is a diffuse white keratotic lesion with numerous raised papules that have red punctate centres. The lesion is usually fissured or wrinkled.

• The raised papules with red centres represent inflamed minor salivary gland ducts.

• Remember that NS, though arising in chronic smokers, is not a potentially malignant disorder. In fact, the epithelium does not show dysplastic changes.

REFERENCES AND FURTHER READING

1. Neville BW, Damm DD, Allen CM, Chi A. Oral and Maxillofacial Pathology. South Asian ed. Elsevier; 2016.

2. Rajendran R, Sivapathasundaram B. Shafer’s Textbook of Oral Pathology. 7th ed. Elsevier; 2012.

3. Sapp JP, Eversole LR, Wysocki GP. Contemporary Oral and Maxillofacial Pathology. 2 nd ed. Mosby; 2004.

4. Regezzi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical Pathologic Correlations. 5 th ed. Elsevier; 2007.

5. Keiles DG. Nicotine Stomatitis. 2016. Available from http://emedicine.medscape.com/article/1076183-overview

6. Marx RE, Stern D. Oral and Maxillofacial Pathology. 1st ed. Quintessence Publishing Co, Inc; 2003.

7. Bharath TS, Kumar NG, Nagaraja A, Saraswathi TR, Babu GS, Raju PR. Palatal changes of reverse smokers in a rural coastal Andhra population with review of literature. J Oral Maxillofac Pathol. 2015;19(2):182-187.

• There are certain red and white oral mucosal lesions that may look like oral lichen planus(OLP) under the microscope! But on a closer look they may lack basal cell degeneration that OLP shows.

• In fact the basal cells may be very much intact and these lesions may possess bulbous rete ridges.

• On a more closer look they may reveal epithelial dysplasia too!

RESEARCH AND HISTORY

In 1978, Krutchkoff and associates, re-examined 223 cases of OLP that were reported to have become malignant.

• However, they reported that only 15 cases were truly OLP and the rest of the lesions only mimicked OLP. They called these lesions lichenoid dysplasia (LD).

• So why did they come to this conclusion? Though these lesions looked like OLP, on close examination, they found that the lesions,

a) lacked basal cell degeneration and in fact had broad and bulbous rete ridges.
b) showed a mixed inflammatory infiltrate having lymphocytes and plasma cells.
c) showed dysplastic features like nuclear pleomorphism & hyperchromasia, disordered stratification, mitotic figures and broad, bulbous rete ridges.

• Since, the lesions had a lichen planus like inflammatory infiltrate or a “Lichenoid” infiltrate and showed epithelial dysplasia, they called them “Lichenoid dysplasia”. According to them, OLP does not show dysplasia.

• Hence they concluded that any lesion clinically diagnosed as OLP, may actually represent LD if it shows dysplasia under the microscope!

IS THIS LESION A DISTINCT ENTITY?

• Well… not exactly. There have been numerous research studies done after their controversial report, and they have only fueled confusion!

• Most pathologists agree that “Lichenoid dysplasia” is a confusing term.

• These lesions may actually represent cases of leukoplakia or erythroplakia, merely in addition to dysplasia, showing a lichenoid infiltrate.

• Thus the need for another term such as “lichenoid dysplasia” may not be warranted.

CONTROVERSY

• That being said, the argument that OLP does not show dysplasia has not reached a common consensus.

• There are reports which claim OLP can manifest dysplasia histologically.

• However pathologists are cautious while making a diagnosis of oral lichen planus, since it has been shown with sufficient evidence that red and white lesions like leukoplakia or erythroplakia may mimic oral lichen planus both clinically and histologically.

It is agreed that using the term “lichenoid dysplasia” to represent such lesions may cause much confusion and they are better acknowledged as epithelial dysplastic lesions showing lichenoid features!  

REFERENCES AND FURTHER READING

1. Krutchkoff DJ, Cutler L, Laskowski S.Oral lichen planus: the evidence regarding potential malignant transformation. J Oral Pathol 1978; 7: 1–7.

2. Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: a distinct histopathologic entity. Oral Surg Oral Med Oral Pathol 1985; 60: 308–15.

3. Lodi G, Scully C, Carrozzo M, Griffiths M, Sugarman PB, Thongprasom K. Current controversies in oral lichen planus: report of an international consensus meeting. Part 2. Clinical management and malignant transformation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100: 164–78.

4. Gonzalez-Moles MA, Scully C, Gil-Montoya JA. Oral lichen planus: controversies surrounding malignant transformation. Oral Dis 2008; 14:229–43.

5. Sanketh DS, Patil S, Swetha B. Oral lichen planus and epithelial dysplasia with lichenoid features: a review and discussion with special reference to diagnosis. J Investig Clin Dent. 2017 Aug;8(3). doi: 10.1111/jicd.12233. Epub 2016 Jul 21.

• The secretory cells present in salivary glands are of two types, called serous and mucous cells.

• These secretory cells, also called acinar cells are housed in secretory end pieces.

• The secretory end pieces are continuous with the main excretory duct of the salivary gland through intermediary ducts. The lumen of the end pieces open into the intercalated duct, which is continuous with the striated duct, which in turn opens into the excretory duct of the salivary gland.

• Also note that the ducts are lined by ductal cells.

MYOEPITHELIAL CELLS

• The secretory end pieces and intercalated ducts are associated with stellate shaped contractile cells called the myoepithelial cells.

• They are located between the basal lamina and the secretory or ductal epithelial cells.

• They are also called “basket cells” because they look like a basket holding a secretory unit.

• The myoepithelial cells have a central body with cytoplasmic extensions embracing the acinar cells.

They are also called “basket cells” because they look like a basket holding a secretory unit. The myoepithelial cells have a central body with cytoplasmic extensions embracing the acinar cells. These cells however, are more fusiform shaped and have lesser cytoplasmic extensions when associated with the ductal cells. The cells are called “myo-epithelial” due to the fact that they are primarily derived from epithelial cells but exhibit certain characteristics of smooth muscle cells.

Structure of Myoepithelial cells

• Myoepithelial cells have a central body with 4-8 cytoplasmic processes. These processes may further branch out to secondary and tertiary processes thus securely hugging the acinar cells.

• They have a flattened nucleus in their cell body with cytoplasmic organelles around it.

• The plasma membrane of the myoepithelial cell has small invaginations called caveolae.

• The myoepithelial cell is attached to the adjacent acinar or ductal cell through desmosomal junctions.

💡NOTE

- It has to be remembered that myoepithelial cells have smooth muscle like properties but are primarily epithelial cells having an ectodermal origin.
- They have features of smooth muscle cells in that they have contractile actin and myosin filaments. However, they also harbour cytokeratin filaments and desmosomal junctions, both characteristic of epithelial cells.

FUNCTIONS

1. The main function of the myoepithelial cell is to contract and help squeeze out secretory products from the secretory end pieces to the ducts and finally to the oral cavity.

2. The repeated contractions of the myoepithelial cell helps in maintaining patency of the ducts.

3. Myoepithelial cells have also been postulated to maintain the structural integrity of the secretory end pieces and the cell polarity of the secretory acinar cells.

4. Interestingly, studies report that myoepithelial cells have a protective function in that they may secrete proteins that may have anti-cancer effects, like tumor-suppressor activity and anti-angiogenic activity. Tumor suppressor activity refers to inhibition of growth of cancerous cells while the anti-angiogenic activity refers to the inhibition of proliferation of blood vessels, which may be a source of nutrition for cancer cells.

5. Another controversial and speculated function of the myoepithelial cell, is the transport of metabolites through the multiple membrane infoldings called the caveolae.

IDENTIFICATION

Myoepithelial cells can be identified through numerous stains and methods like hematoxylin and eosin stains, fluorescent stains, special stains like silver staining and immunohistochemical markers like α-SMA, CK-14, CK-17,calponin, integrin and p63.

REFERENCES AND FURTHER READING

1. Chitturi RT, Veeravarmal V, Nirmal RM, Reddy BV. Myoepithelial Cells (MEC) of the Salivary Glands in Health and Tumours. J Clin Diagn Res. 2015 Mar;9(3):ZE14-8.

2. Shah AA, Mulla AF, Mayank M. Pathophysiology of myoepithelial cells in salivary glands. J Oral Maxillofac Pathol. 2016 ;20(3):480-490.

3. Nanci A. Tencate’s Oral Histology. Development, Structure and Function. 8th ed. Elsevier;2013.

4. Kumar GS. Orban’s Oral Histology and Embryology.13th ed. Elsevier;2011.

5. Avery JK.Oral development and Histology.3rd ed. Thieme Medical Publishers;2002.

This video covers the classification, structure and the histology of the secretory cells and ducts of the salivary gland. I have split the whole video topic into two notes - one covering it's classification and structure and the other explaining the histology of the secretory cells and ducts.

• Salivary glands (SG) are compound, exocrine glands whose function is to secrete saliva.

• Saliva, 90% of which is secreted by major salivary glands (which we shall discuss subsequently), is a multifunctional fluid, helping in maintaining the integrity of the oral cavity in various ways.

SECRETORY/ACINAR CELLS

Serous cell

• Serous cells are housed in a spherical acinus and may be 8-12 in number surrounding a central lumen.

• A serous cell is pyramid shaped with a basal nucleus and numerous secretory granules in the apical cytoplasm.

• These granules are called zymogen granules and house salivary macromolecules or proteins.

• The lumen of the serous acinus has finger-like extensions that continue between the serous cells. These extensions are called canaliculi.

• The cells are joined to each other on their lateral surfaces through junctional complexes. Each junctional complex is made of a tight junction (zona occludens), an adhering junction (zonula adherens) and a desmosome (macula adherens).

Mucous cell

• Mucous acinar cells are also pyramidal cells with the apical cytoplasm packed with mucin granules and a flat nucleus in the basal cytoplasm compressed by mucin granules.

• These cells are housed in tubular secretory end pieces and a cross section would show mucous acinar cells surrounding a central lumen.

• Sometimes, mucous acini or end pieces may be associated with serous cells arranged on the them in the shape of a crescent. This is called a serous demilune.

• Serous demilunes are much like serous acini.

• Unlike, serous acini, mucous acini lack intercellular canaliculi.

• However, those mucous acini associated with serous demilunes have canaliculi and the secretions of these serous demilunes reach the lumen of the end pieces through these canaliculi.

💡KNOW THY FACTS

Under the light microscope, the mucin granules/ mucin cannot be seen in H & E preparations, since they get washed out. Hence the cells look empty when stained with H & E stains. However, special stains like periodic acid-Schiff and alcian blue can stain mucin/mucus.

DUCTS AND DUCTAL CELLS

Intercalated duct

• Secretory end pieces are continuous with the intercalated ducts.

• Intercalated ducts are lined by simple cuboidal epithelium and are associated with myoepithelial cells.

• The intercalated duct cells have a central nucleus and little cytoplasm.

• Intercalated ducts are very small and are usually not visible under the microscope.

• Several intercalated ducts join and open into striated ducts.

Striated duct

• Striated ducts are lined by columnar cells which have a centrally placed nucleus and an eosinophilic cytoplasm.

• The basal end of the striated ductal cell is thrown into numerous deep folds housing several mitochondria. These deep folds give the basal surface of the cell a striated appearance under the microscope, hence the name.

• These ducts form the main portion of the salivary gland ductal system and are responsible for most of the ionic transport happening in the saliva when it travels from the end piece to the oral cavity.

• This process requires a lot of energy and this is why these cells possess several mitochondria in the basal folds of their cytoplasm.

Excretory duct

• Excretory ducts are present in the connective tissue septa between lobules and are called inter-lobular ducts.

• Interlobular excretory ducts fuse to form bigger inter-lobar excretory ducts, with the main excretory duct opening into the oral cavity.

• The inter-lobular excretory ducts are lined by pseudo-stratified columnar epithelium, and as the ducts get larger and approach the oral cavity, the lining becomes stratified squamous.

REFERENCES AND FURTHER READING

1. Berkovitz BKB, Hollan GR, Moxham BJ. Oral Anatomy, Histology and Embryology. 4th ed. Mosby Elsevier; 2009.

2. Nanci A. Tencate’s Oral Histology. Development, Structure and Function. 8th ed. Elsevier; 2013.

3. Kumar GS. Orban’s Oral Histology and Embryology.13th ed. Elsevier; 2011.

4. Avery JK. Oral development and Histology. 3rd ed. Thieme Medical Publishers; 2002.

This video covers the classification, structure and the histology of the secretory cells and ducts of the salivary gland. I have split the whole video topic into two notes - one covering it's classification and structure and the other explaining the histology of the secretory cells and ducts.

• Salivary glands (SG) are compound, exocrine glands whose function is to secrete saliva.

• Saliva, 90% of which is secreted by major salivary glands (which we shall discuss subsequently), is a multifunctional fluid, helping in maintaining the integrity of the oral cavity in various ways.

💡FUNCTIONS OF SALIVA

- The mucin in the saliva plays a major role in lubrication. This helps in prevention of oral tissues adhering to one another (keeps tissue moist). As a whole this helps in mastication, deglutition(swallowing) and speech.
- The buffering action of saliva, as a result of the presence of bicarbonate and phosphate ions, help in maintaining integrity of the teeth (protects from demineralization, promotes remineralization if demineralized).
- Proteins like lactoferrin and lysozyme in saliva have anti-bacterial action.
- Saliva helps in food digestion (amylase and lipase).
- Immunoglobulin A (IgA) is actively secreted in saliva. It contributes to mucosal immunity.

CLASSIFICATION OF SALIVARY GLANDS

SGs can be classified according to their size and the secretory cells they posses.

According to size

• Major salivary glands

• Minor salivary glands

Major salivary glands comprise 3 pairs of glands them being,

• Parotid glands

• Submandibular glands

• Sublingual glands

Minor salivary glands are scattered throughout the oral cavity and are named according to their location.

• Labial glands

• Buccal glands

• Palatal glands

• Lingual glands (von Ebner’s glands)

• Glossopalatine glands

• Retromolar glands

💡KNOW THY FACTS

- The minor salivary glands are at least 600-1000 in number.
- The minor glands only contribute 10% of the total salivary secretion.
- Most minor salivary glands are predominantly mucous glands, with the exception of von Ebner's glands that are purely serous.
- Minor glands are not found on the gingiva and anterior hard palate.

According to type of “secretory cell”

SGs can be

• Purely serous

• Purely mucous

• Mixed serous-mucous with either of the secretory cell predominating.

- Parotid glands are serous, 
- Submandibular glands are mixed but are predominantly serous and 
- Sublingual glands are also mixed but predominantly mucous. 
- Majority of the minor salivary glands are mucous except for von Ebners glands which are serous glands.

STRUCTURE OF SALIVARY GLANDS

Secretory cells

• SGs are made of secretory units called “acini“ (singular - acinus), that house secretory cells.

• Secretory cells are of two types - serous and mucous secretory cells.

• Since secretory (serous and mucous) cells are housed in an acinus, the cells are also collectively called “acinar cells“.

• The secretory units communicate with the oral cavity through a complex ductal arrangement.

• The secretory cells (acinar cells) are responsible for secreting the primary salivary secretion.

Ductal arrangement

• Secretory units open into an “intercalated duct“, which is continuous with the “striated duct“, which in turn opens into the “excretory duct“ of the salivary gland.

• The ducts like the secretory units, are lined by cells called ductal cells.

• The saliva secreted by acinar cells pass through the ducts to be excreted finally via the excretory duct into the oral cavity.

• On it’s way, the saliva’s composition is influenced or affected by the intercalated and striated ducts.

Myoepithelial cells

• The secretory end pieces and intercalated ducts are associated with stellate shaped contractile cells called the myoepithelial cells.

• They are also called “basket cells” because they look like a basket holding a secretory unit.

• Myoepithelial cells are epithelial cells that also have smooth muscle like contractile properties.

• The main function of the myoepithelial cell is to contract and help squeeze out secretory products from the secretory end pieces to the ducts and finally to the oral cavity.

💡KNOW THY FACTS

This architecture of the salivary glands can be compared to a bunch of grapes, where the grapes represent the secretory end pieces (acini) and the stem/branches represent the ducts.

LOBULAR ARCHITECTURE

• Salivary glands are basically enclosed by a connective tissue capsule that branches into inter-lobar septa (singular-septum) to divide the parenchyma/functional tissues into lobes.

• These lobes are further divided by inter-lobular septa into lobules.

• A lobule houses secretory end pieces, the intercalated and the striated ducts. Hence intercalated and striated ducts are called intra-lobular ducts.Striated ducts continue to open into excretory ducts in between lobules.

• Excretory ducts in between lobules are inter-lobular excretory ducts. These continue and join other inter-lobular excretory ducts to form inter-lobar excretory ducts which in turn finally open into the main excretory duct of the salivary gland that is continuous with the oral cavity.

A NOTE ON ONCOCYTES

• Oncocytes are cells that are packed with mitochondria and appear granular and deep pink under the microscope.

• Oncocytes could appear in the acini and ducts of normal salivary glands.

• The number of oncocytes in the salivary gland increase with age.

HIGHLIGHTS - VIVA & ENTRANCE EXAM PERSPECTIVE

• SGs are made of secretory units called “acini“ (singular - acinus), that house secretory cells.

• Secretory cells are of two types - serous and mucous secretory cells.

• Since secretory (serous and mucous) cells are housed in an acinus, the cells are also collectively called “acinar cells“.

• Secretory units open into an “intercalated duct“, which is continuous with the “striated duct“, which in turn opens into the “excretory duct“ of the salivary gland.

• The ducts like the secretory units, are lined by cells called ductal cells.

• The secretory end pieces and intercalated ducts are associated with stellate shaped contractile cells called the myoepithelial cells.

• They are also called “basket cells” because they look like a basket holding a secretory unit.

• Myoepithelial cells are epithelial cells that also have smooth muscle like contractile properties.

• Major salivary glands comprise 3 pairs of glands them being, -> a) Parotid glands, b) Submandibular glands, c) Sublingual glands.

• Parotid glands are serous, submandibular glands are mixed but are predominantly serous and sublingual glands are also mixed but predominantly mucous.

• Majority of the minor salivary glands are mucous except for von Ebners glands which are serous glands.

REFERENCES AND FURTHER READING

1. Berkovitz BKB, Hollan GR, Moxham BJ. Oral Anatomy, Histology and Embryology. 4^th ed. Mosby Elsevier; 2009.

2. Nanci A. Tencate’s Oral Histology. Development, Structure and Function. 8^th ed. Elsevier; 2013.

3. Kumar GS. Orban’s Oral Histology and Embryology.13^th ed. Elsevier; 2011.

4. Avery JK. Oral development and Histology. 3^rd ed. Thieme Medical Publishers; 2002.