Diseases of Salivary Glands II

* Today we will continue the bone diseases;

Sialadenosis
Which is also called "sialosis": it's defined as Non-inflammatory, non-neoplastic, recurrent bilateral swelling of salivary glands. So it's not a tumor, no infection no inflammation, it's JUST hyperplastic change in the salivary gland and usually in the Parotid Gland (all serous cells). - The cause may be due to: 1- Abnormalities of neurosecretory control, the innervations "nerve supply to the glands" may have sth wrong. 2- It may be due to malnutrition 3- Liver cirrhosis 4- Chronic alcoholism 5- Some drugs have side effect on Sialadenosis. 6- Hormonal disturbances. - So we see neither tumor nor inflammation... We see hypertrophy of serous acinar cells which will reach twice of its normal size the Cytoplasm is densely packed with secretory granules which are normally present in serous cells. So we see the serous cells dark in color (purple) due to the secretory granules. >> So if U encounter a patient with bilateral enlargement of the parotid glands, chronic term, and the patient isn't having Sjgren Syndrome (because as we said 30% of Sjgren Syndrome patients will have parotid gland enlargement), U can ask the patient if he has any of the causes 'mentioned above' .. So the patient will have Sialadenosis. <<<

HIV-Associated Salivary Gland Disease

HIV patients have changes in their parotid glands; these changes include myoepithelial sialadenitis & xerostomia. So we will have It may be Xerostomia in AIDS patients which is due to infiltrate by lymphocytes which looks like Sjgren Syndrome but Xerostomia will not have autoantibody like Sjgren Syndrome.

-Q: Why the AIDS patient will have a lymphocytic infiltration while he is having a decrease number of T-lymphocytes (decrease in CD4 count)?? -A: although we have decrease in number of CD4 but still we have some lymphocytes aren't functioning like CD4+, but they will infiltrate the salivary glands causing Xerostomia.

- There may be myoepithelial sialadenitis: in normal salivary glands we'll see ducts lined by epithelium, lobules composed of serous cells or mucous cells or mixed and stroma. The inflammatory infiltrate will go in between the lobules and the ducts will have a proliferation of the epithelium forming islands of epithelium with no spaces in between (they closed the ducts). This proliferation is thought to be myoepithelial cells which surround the ducts. Then the ducts will close. >> Sialadenitis means inflammation inflammation means infiltration of lymphocytes...<<< >> In brief: myoepithelial sialadenitis: it's infiltration of salivary gland tissue with lymphocytes & proliferation of myoepithelial cells. So in AIDS patient there will be no auto antibodies. (If U don't understand it well... Please refer to the previous lecture bcz it has been discussed in details ) -Another finding is Lymphadenopathy: we know in AIDS patients there is persistent generalized lymphadenpathy. So we'll have enlargement of lymph nodes in the parotid glands >> enlargement of parotid glands. - Other finding is the presence of multiple lymphoepithelial cysts: we know on the lateral border of the tongue there is a collection of lymphoid tissue & on the soft palate. In these sites we may have lymphoepithelial cyst. This cyst might be extraorally in the neck & it's called cervical lymphoepithelial cyst. - The etiology of this cyst is entrapment of epithelium within the lymph node. The cause why AIDS patients will have multiple lymphoepithelial cyst isn't really clear but it's one of the changes happened with them. *So the causes of enlargement of parotid glands in AIDS patients: 1-myoepithelial sialadenitis which looks like Sjgren Syndrome but it has no auto antibodies. 2-lymph node enlargement inside the parotid gland

3-lymphoepithelial cysts.

Salivary gland tumors

- They are benign & malignant, but in general they are uncommon with geographic variation. Tumors in major salivary glands are more common than in minor glands (which contribute to 15-20 % from all salivary gland tumors). - The most frequent site for tumors in major salivary glands is the Parotid Glands (nearly 90% of all major glands tumors). In the submandibular gland it's nearly 10%, but very rare in sublingual. - In minor glands: 55% of tumors occurring in the Palate, followed by the upper lip 22%, the rest will be scattered in the lower lip & lateral border of the tongue & buccal mucosa. - If we have a lesion in the lower lip, I'll think first about mucocele (reactive changes). But if there is a lesion in the upper lip I'll think first of tumors (benign or malignant). - Although the parotid glands have the highest percentage of tumors, most of these tumors are benign ones. But most of minor glands tumors are Malignant. * Some of the tumors occur inside the bone due to: 1- Entrapment of salivary gland tissue during development within the bone. 2- The lining of the cyst may have mucous metaplasia & these mucous cells may give malignant tumors like mucoepidormoid carcinoma & glandular odontogenic cysts.

CLASSIFICATIONS OF TUMORS: ADENOMA OR CARCINOMA.

We will start with the first type of adenoma "Pleomorphic adenoma" This type of tumor is also called "Mixed Tumor"; it's a benign tumor, & the commonest tumor of all salivary gland tumors. It occurs most of the time in the Parotid Glands, it also occurs in the Minor salivary glands, & the most common site in the minor is the Palate. It's a Benign tumor so there will be a slowly growing, it doesn't have ulceration unless it has been secondarily traumatized, not like the Malignant which will have a rapidly growing and aggressive and may have surface ulceration. It's also well defined tumor, painless, rubbery swelling with intact overlying skin or mucosa & the patient may be aware of lesion for several years because it is slowly growing.

Picture in slide 13 a swelling in the upper lip turned to be a Pleomorphic

adenoma.
****Histopathologic Features * Composed of cells of epithelial and myoepithelial origin. We have cellular component & matrix component. The cellular component will be epithelial and myoepithelial. Epitheliums produce keratin. * these 2 cell types can't be differentiated by the stain,, so we should depends on their location, one surrounds the duct & the other will be clustered in islands form. But if you want to determine accurately which is which you should use a special type of stains in immunohistochemistry called (S100 or smooth muscle actin) * The difference between them is in the function, Myoepithelial cells have some features like the smooth muscle cells, they have actine & other proteins & antigens like the smooth muscle cells, but they retain some epithelial features. That's why they are called Myoepithelial. Their function is to press on the ducts so the secretion will go out. These cells will form ductal spaces surrounded first by epithelial then myoepithelial cells (which it's most likely to be like islands). The myoepithelial cells will be in different forms: clusters, sheets, spindle like or plasma cytoids appearance. * The plasma cytoid: like in multiple myeloma, the plasma cells will have a plenty of cytoplasm & the nucleus is ec-centric (not in the center). So in the Pleomorphic adenoma we will have an appearance like plasma cytoid. We aren't having plasma cells but the appearance looks like them. ** The Matrix is Mesenchyme like matrix and has different features, for example it has fibroblast which will produce fibers (collagen), and it also has bone products osteiod, the cartilage has products chondroid, we also have blood vessels. And we also have myxoid like matrix. (Myxoid means loose thin fibers with a lot of delicate material within it (glycosaminoglycans), it's mucous like but with fibers) In the matrix we can see chondroid like matrix, osteiod like matrix, myxoid like matrix >>> so we see variable pictures of mesenchyme like products, but they aren't actually mesenchyme. These products come from the myoepithelial cells. Concentrate on the word "LIKE", chondroid like osteiod like myxoid likefibroblast like (products). So pleomorphic refers to different features that can be seen in the matrix which is produced by the myoepithelial cells.

* Sometimes the matrix will be hyalinized (very pink) it looks like dense collagen; it's a product of myoepithelial cells. * So in this picture you can see a duct surrounded by epithelial lining then a cluster of myoepithelial cells.

The myoepithelial cells can be plasma cytoid like cells. Appears dark in the picture. And this dark part is the peripheral nucleus. They are secreting myxoid like matrix & the matrix is between them.

* The pleomorphic adenoma sometimes is encapsulated & sometimes the capsule isn't well formed >> here the lesion isn't encapsulated but it's well demarcated, I can identify it. Most of the time we don't have the formed capsule.

* In this picture we can say its well demarcated tumor. * Sometimes the dense fibrous tissue it's not continuous, we can see nodules of the tumor outside the demarcation which it's not infiltration because when they took serial section they found that these nodules are connected to the main tumor. For this reason

>>> the surgeon should take a safe margin when removing the lesion to avoid the recurrence. * Here we see a chondroid like matrix, surround the myoepithelial cells which secrete the chondroid. .

* Here we see a myxoid like matrix it's called like this because of the high percentage of (glycosaminoglycans) giving it the loose appearance, we also have the myoepithelial cells which secrete stroma. This type of tumor tend to rupture easily during the surgical removal >> so it has a high recurrence rate compared to other types. This type may also be incorporated with chondroid component so we call it "myxochondroid tissue". This type also has malignant transformation, usually in tumors present for many years.

* The epithelial cells may have squamous metaplasia & they may form keratin looks like keratin pearls within the pleomorphic adenoma.

Keratin pearl

* We may have variable appearances within the same tumor. ** In brief: the myoepithelial cells in pleomorphic adenoma have several appearances & have several types of products. These appearances are: plasma cells like shape, cuboidal and spindle like. The types of products are: myxoid, chondroid, hyalinized and sometimes osteoid. The second type of Adenoma is:

Warthin Tumor (Papillary Cystadenoma Lymphomatosum)

Is another benign tumor, a long term "papillary cystadenoma lymphomatosum" but descriptive of the lesion. Papillary: because we have papillary component. Cyst : because we have cyst component with papillary projections inside it. Adenoma: because it is a benign tumor of epithelial cells, "adenoma: a benign tumor specifically of glandular tissue". Lymphomatosum : because it has a dense lymphoid component with germinal centers. >> So Warthin Tumor: benign, cystic, having papillary projections, adenoma, with dense lymphoid tissue. It is interesting because it may occur bilaterally in the parotid glands It occurs almost exclusively in the parotid. It occurs mainly in males, in the elderly, some books also relate it to smoking. It's slowly growing * The origin of the lymphoid component is the lymph nodes entrapped within the parotid gland. Lymph nodes may have epithelial entrapment within them which gave us the lymphoepithelial cyst as we said before. But glandular epithelial entrapment within the lymphoid tissue will give us this tumor "Warthin Tumor". This is a slowly enlarging tumor of the parotid gland, we should think of Pleomorphic Adenoma 1st and then warthin tumor. The lesion when it is cut, grossly it has cystic spaces filled with mucoid material.

* Microscopically you will see cystic spaces. Each empty space in the picture is a cystic space; lined by columnar cells those cells are having an Oncocytic appearance "Oncocytic appearance means that we have a special type of cells that has a lot of mitochondria in the cytoplasm" This tumor even may have germinal centers, which is one of the features of lymph nodes; because this germinal center is found in lymph nodes, they think that it was a lymph node with entrapped epithelium

Germinal center

* As we can see in the picture; we have a space "cyst" with papillary projection "the polyp protruding in the space" it demonstrates the papillary part of the lesion that is why we call it papillary-cyst-adenoma {benign tumor} lymphomatosum {it has densely packed lymphocytes with germinal centers that looks like the lymphoid tissue} And in the picture the lining is double layered we have columnar cells and cuboidal cells. We have lymphoid component the epithelial component has packed mitochondria Cystic spaces most of the time can't be seen grossly but it is in general a space empty or containing a mucous like material surrounded by epithelium, and they are of variable sizes, sometimes they're big sometimes they're small, sometimes we have the papillary projections within them, and sometimes we don't

The third type of Adenoma is:

Basal Cell Adenoma:

* A benign tumor of Salivary Glands, it composes a little percentage of all SG tumors It is called Basal Cell adenoma because it is composed of small cuboidal cells that look like the basal cells *basal cells are usually cuboidal and small * You may ask: does it have myoepithelial cells? Myoepithelial cells here are very very limited; it is composed mainly of basal cells, which are epithelial cells Mainly in the parotid, or the upper lip Uniform small basaloid cells. * They are arranged in variable patterns may be small may be strands and usually in clusters not as individual scattered cells * It is well encapsulated not like the pleomorphic adenoma which is not well-encapsulated

The fourth type of adenoma is:

Oncocytoma:
With age salivary glands cells will have more oncocytes {which are epithelial cells packed
with a lot of mitochondria} so elderly have oncocytosis sometimes which is a diffused change of the SG (age changes) BUT when these oncocytes form a well defined mass it will be called Oncocytoma *It is a rare tumor *usually in parotid *with thin capsule. Oncocytes: Large cells with granular eosinophilic cytoplasm rich in mitochondria .So the differential diagnosis (D/D) for it oncocytic hyperplasia which is considered an age change. ** NOTE** when the Dr. says true benign tumor she means or she want to stress on the fact that it is a tumor with actual defect in the cells cycle program not that there is pseudo benign tumor, the "TRUE" word to emphasize the fact that it has disturbance in the growth potential.

The fifth type of adenoma is:

Canalicular Adenoma:
Is another epithelial tumor, but here the cells are columnar or cuboidal and the stroma supporting these cells is a very loose myxoid stroma and it is called "canalicular" due to the canals "spaces" that surround by the neoplastic cells. We can't even see the fibers in this stroma, it is very loose So canalicular adenoma is columnar cells forming a canal like space and lying in a loose myxoid like stroma The stroma of the canalicular adenoma may have cystic degeneration, and it may go away; and you find nothing between the cells! !!So when you study these tumors you should understand the neoplastic component, the morphology of the cells, the appearance, and the pattern that the cells are aligned in, and what the stroma of this tumor is. !! The sixth type of adenoma is:

Ductal Papillomas:
Suppose we had papillary projections inside the duct... Sometime in Warthin Tumor we see this appearance; a lot of papillary projections inside the cystic space And when you cut these papillary projections they look like islands floating in nothing AND when these papillary projection exist within the same duct "a single duct" they are called Ductal Papilloma It has several subtypes we will not talk about them. So Ductal Papilloma papillary like projections; projecting within a duct and it is a benign tumor.

NOW WE WILL START WITH THE MALIGNANT TUMORS

* Malignant tumors of SG are Uncommon Less than 1% of all of the malignancies of the body In the head and neck about 5% of all head and neck cancers Mostly affecting the major, especially the parotid ** NOTE ** most of the minor salivary glands tumors are malignant But the malignant tumors of SG most occurring in the Major "Polymorphous Low Grade Adenocarcinoma" the book talks about it but the Dr. Doesn't want us to know that much about because it has been discovered late in the 80s and the pathologists can't diagnose it well so you don't have to know about it that much ... Now the first type is: Mucoepidermoid Carcinoma: The most common malignant SG tumor and it is interesting because it may occur in children, it may occur inside the bone, and it may occur bilaterally occasionally. From its name it has three cellular components two in the name "and one is hiding :P" * Muco: mucous cells. * Epidermoid: squamousoid epithelial cells "7urshofeyyah" so they are flattened cells. - The 3rd one is the intermediate component "cells". The books say that the intermediate cells are the progenitor cells that will give the mucous cells and the epidermoid cells In the mucoepidermoid carcinoma we have three grades: Low, intermediate, and high. The high grade MEC is highly aggressive. ** High grade MEC will have pleomorphic features of the cells, hypercromatism, high mitotic figures, variations in the size and shape of the cells, all the signs of aggressive tumors. The high grade MEC will not have the mucous component; we can't see mucous cells in it, except very rare, except with special stains but most of the tumor will be the intermediate component having all of the neoplastic features ** But the Low grade MEC will have cystic spaces, high mucous component, some epidermal component, and little or no intermediate component.

|| the more the intermediate component, and the less the mucous component, the more the aggressive the tumor and of higher grade||

If we have a low grade MEC it will behave like a benign tumor, so it will be slowly growing with little or no ulceration, because it is of low grade But if we have a high grade tumor it will be aggressively growing, perforating bones, causing ulcerations of the over lying mucosa * So we should know the clinical pictures of both high and low grade MEC, and the histologic pictures and features of both as well. Mucous component is high in >> Low grade Cystic component is high in >> Low grade High mitotic figures, pleomorphism, hypercromatism high in >> high grade Low or no mucous component >> high grade It is interesting because it may occur inside the bone >> so most of the intra-boney SG tumors are MEC.

* In the picture we have a cystic space {the empty space above} lined by epithelium which is composed of mucous cells and they are abundant, so we call this tumor low grade MEC

* In the picture we have mucous and other components some of them may be intermediate but they have no hypercromatism, no pleomorphism, so it is low grade MEC

* Here we have squamoid components maybe! Flattened, with intermediate cells So it's High grade!!

We should be able to distinguish between the high and low, the intermediate comes in between we don't have to really know how it is High grade is an ugly tumor it can be very aggressive, sometimes it cannot be differentiated from high grade squamous cell carcinoma (SCC) because sometimes you cannot identify any mucous cells High grade tumors have "low" survival rate, low grade have better prognosis they have good survival rate. The second type is:

Acinic Cell Carcinoma:

* It is considered as a low grade malignancy, it occurs mainly in the parotid gland, it has very good survival rate, although it is malignant! It is uncommon It can occur in other locations such as the upper lip The cells; acinic cells look like serous cells which are packed with granules So they look purple, so they have dark cytoplasm not like mucous cells which have very pale cytoplasm. The third type is:

Adenoid Cystic Carcinoma:

It is aggressive, it likes nerves so it proliferates surrounding the nerves trunks So it has bad clinical features because it tends to invade and proliferate the nerves and spread along the nerve so not just within blood vessels and lymphatic it goes within the nerves. So it can reach the lungs easily and any other locations alongside the nerves What distinguishes the adenoid cystic carcinoma clinically is that the survival rate is okay when it's 5 years it is not that bad But if the patient lives after 5 years the 10 years survival rate is low, most of the patients will die, 15 years survival rate is even lower!! It has high recurrent rate it is aggressive even though the cells look bland so when you look at them microscopically they are small, rounded, cuboidal, I can't see mitotic figures

I cannot see variation in staining shape and characteristics they are bland but it is aggressive

The characteristic histological feature of these small cuboidal cells is the "Swiss cheese" pattern formation several cribriform spaces surrounded by small bland cells And it has stroma surrounding it; which is variable, it may be hyalinized it may be loose

In the picture we have a nerve, the dark cells are the tumor cells and they are going inside the nerve, and they will metastasize along the nerve in addition to the other ways of metastasis notice how they are forming a concentric rings surrounding the nerve bundle

These bland cells may form several cribriform spaces they may form bundles of cells, or strands of cells so they can give several appearances But the most common is the cribriform appearance

So we have Perineural invasion in the Adenoid Cystic Carcinoma Long term prognosis is poor. 5-year survival rates for parotid tumors are 75%, 10-year rates are 40%, 20-year are <15%, most of them will die

The fourth type is:

Carcinoma Arising in Pleomorphic Adenoma

Here we have to know that long standing pleomorphic adenoma may have carcinoma arising in it, and that is why we said we don't like to leave it without removing it because long standing adenoma may have carcinomatous changes.

Polymorphous Low Grade Adenocarcinoma as I said before we will not talk about it Other Salivary Carcinomas... Also forget about them

We have Age *Changes in Salivary Glands:

People will have more adipose tissue in the parotid gland replacing the acini that were there, so the serous component will decrease. And there may be Oncocytic hyperplasia within the parotid gland The secretions will decrease also with time.

Finished Alhamdulelah
We did our best so forgive us for any mistake

Done By: Ayah M. Tareef & Nada Nammas Big thank to our friend & "sister" Duaa Walid Abu Hmaid

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