Diagnosis of Sjogren syndrome

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Diagnosis of Sjogren syndrome Powered By Docstoc
					Unless stated otherwise, the general term Sjögren syndrome
(SS) is used to encompass both types.

Both of these forms of Sjögren’s syndrome, primary and
secondary, shows a spectrum of clinical features with
widespread involvement of other glands and other tissues.
We said first the main involvement is in salivary and
lacrimary glands; we get the xerostimia and xerophthalmia.
Some of these patients might get involvement in the skin;
they get xeroderma (dry skin), respiratory tract where mucus
is secreted might become dry also. Now in Extra glandular
and Rheumatoid arthritis is seen in secondary Sjögren’s
syndrome, renal tubular defects.


     Diagnosis of Sjogren syndrome

Now there is a criteria to diagnose Sjögren’s syndrome
because of its variety of clinical features, at least 4 out of
these 6 features need to be found to get diagnosed having
Sjögren’s syndrome:

  • Ocular symptoms.
  • Ocular signs: things that are seen. (What is the
    difference between symptoms and signs? The patients
    feels the symptoms while the doctors sees the signs, for
    example pain is a symptom)
  • Oral symptoms: they are xerostimia and the results of
    xerostimia.
  • Salivary gland function: how much did the salivary
    flow reduce.
  • Labial salivary gland biopsy: we might need to get it to
    see the infiltrates.
  • Also serological findings show Ro and La
    autoantibodies.

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Like other autoimmune diseases, most of these diseases
affect middle-aged females with a ratio of 9:1. The most
common symptoms are related to xerostomia and
xerophthalmia. In general with primary Sjögren you get
more severe xerostomia and xerophthalmia.


          CLINICAL MANIFESTATION

Remember the function of saliva? What are the functions of
saliva?
   1) Lubrication of the mucosal surfaces
   2) Speech
   3) Swallowing
   4) Antimicrobial effect,
      cleaning and flushing.

     In xerostomia the patient
     will have difficulty to eat ,
     speak, swallow. They have
     to sip fluid all the time.
     There will be increased rate
     of dental caries. Look at this
     patient he has cervical
     caries, and look at this gingiva how its shiny – that’s
     because its dry. They are more prone into fungal
     infection (candidosis). They might also get acute
     bacterial sialadenitis.

Now look at the buccal and
lingual mucosa, its atrophic and
if you stick a mouth mirror to
the mucosa it wont be easy to
remove.

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It will also show
some fissuring and lobulation.

The eyes will appear red and dry, the patient will have a
feeling of gritty in the eyes, and gritty means there is
something like sand in their eyes. It’s very annoying. They
can get rid of these symptoms by the use of artificial tears.

 Salivary glands enlargement will be variable.
Its usually bilateral, and in the patients photo
It’s a parotid enlargement. Sometimes it
disappears after a while. 30% of patients give
history of enlargement.

Now for Lacrimal gland enlargement, you
know the lacrimal gland contains the tears.
Its uncommon, and when it happens the eyes will be
pushed a little bit, Although clinical involvement of minor
salivary glands is uncommon, they are often involved
microscopically.


       HISTOLOGICAL MANIFESTATION

The major glands show diffused lymphocytic infiltrates,
around the intralobular ducts and eventually they cause
replacement of the parenchyma of the gland. The acini will
undergo atrophy.

When they studied these cells they found
 1) 20% B cells
 2) 80% T cells, mostly T-helper.

The ducts doesn’t get atrophied from the beginning, the
acini disappear first. Then the ducts Proliferate to form

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epimyoepithelial islands. When they examined this they
found that these cells are epithelial and myoepithelial cells
together.
They will call this lesion myoepithelial sialadenitis (because
we have chronic infiltrate of lymphocytic cells) or benign
lymphoepithelial lesion.

We have to carefully examine because it’s like lymphoma,
but unlike lymphoma, the infiltrate does not cross-
interlobular connective tissue septa. The parenchyma is
destroyed and they still have this lobular architecture.

Now the minor glands this is the lobular architecture of it
we still have the connective tissue septal and these are the
lobules. There is diffuse lymphocytic infiltration, now in
minor salivary glands just a focus of 40 or 50 cells will be
adequate for us to diagnose that. The number of foci reflects
the severity of the disease. Again for minor glands there is
atrophy in the acini.

Q: Which is better to house the lymphocytes? Parotid gland
or minor glands?
A: Minor is better, because the parotid contains the facial
nerve.




                              Now other investigations that
                              they can do in addition to
                              salivary gland biopsy, they can
                              estimate the salivary flow rates
                              and these are usually reduced.
                              Also they can do a Sialogram
                              for a gland, it’s a radiograph of


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it. They take it after injecting something inside the gland
that can be seen in the radiograph. They wait a little bit
until the duct and the tissue take them. The appearance will
be like a cherry tree in blossom.
Or they might also call it the
snowstorm appearance. This factor
is associated
with the dilatation of duct, normally
the ductal morphology wont be like
this.

They can also use the radioactive material 99Tcm which will
show reduced uptake.

There are also a lot of serological findings but the most
important thing is antibodies known as:
  • Anti SSA = anti ro
  • anti SSB = anti-La.

Now we use for our criteria, remember the 6 criteria above?

Again the dr. showed a table and it showed the serological
findings and she said no need to memories the numbers but
just understand whats happening here.

 Like other connective tissue diseases, we have serological
abnormalities. There is elevated ESR,
Hypergammaglobulinemia means that there is increase in
antibody titer. Its not specific. There is Elevation in ß2
microglobulin this is increased in exacerbations. Now we
come to the profile of autoantibodies, we have the
Rheumatoid factor its mostly seen in secondary disease.
And these one I already spoke about, Anti-Ro/anti-La




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For these antibodies, although neither anti-Ro nor anti-La is
specific for Sjögren’s Syndrome, they are very helpful. They
help in the diagnosis of the disease and the onset of it.


       ETIOLOGY AND PATHOGENESIS

Although Sjögren Syndrome is highly related to the
autoimmune disease, what triggers it? Are they genetic?

  1) Maybe not strictly genetic but they can be genetic. It
     occurs with increased frequency in patients with
     certain HLA class II MHC genes.

  2) Also some viruses are thought to be affecting this
     disease, especially EBV has been suggested as
     potential trigger factors.

  3) Immunological mechanisms leading to destruction of
     glandular tissue probably involve mainly T cells and
     their cytokines.

  4) We are uncertain of the pathogenic significance of the
     range of circulating autoantibodies, their formation is
     triggered by something we don’t know it. When you
     say it is autoimmune you are saying something about
     the pathogenesis of the disease but the initial
     etiological factors remains unknown.




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    MALIGNANT TRANSFORMATION
The problem of Sjögren Syndrome the uncomfort and
suffering of the patient a certain percentage of these patients
might get lymphoma. The lymphoma here is B cell. You
know there are interactions between B cells and T cells.
Here this is hyper stimulation of B cells.

The risk varies from <1%-6% of Sjögren Syndrome patients.
Risk of B cell lymphoma developing in affected gland 44
times that of general population. Risk may be greater in
primary Sjögren Syndrome than secondary Sjögren
Syndrome.

Malignant transformation usually occurs later in the course
of disease. It may be may be associated with increased
swelling of gland, like the parotid for example.

Did you hear about MALT lymphoma? (mucosal associated
lymphoid tissue)

Initially it starts as a MALT lymphoma, prolonged and low-
grade lymphoma, but then it might become more
aggressive. When we have slowly progressive lymphoma its
difficult to treat.




Now we will talk about Sialadenitis, sometimes certain
patients get bilateral enlargement of a salivary gland, its
asymptomatic.



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We don’t know why, and they don’t have Sjögren
Syndrome. It might affect the parotid gland. There is
hypertrophy of the acini (about twice the size of the normal
cells), which results in total hypertrophy of the gland. This
has been reported in patients with:

  •   Hormonal disturbances.
  •   Malnutrition.
  •   Liver cirrhosis.
  •   Chronic alcoholism.
  •   Various drugs.

There are probably abnormalities in neurosecretory control.
If you ask about medical history he might have diabetes.

  People with HIV disease also get salivary gland disease.
  Prevalence of HIV disease involvement with salivary
  glands is higher in children than adults. They might get
  xerostomia and swelling of major glands. They get
  myoepithelial cells same as the ones in Sjögren
  Syndrome. But they don’t have the same antibodies in
  Sjögren Syndrome. Also HIV related MALT enlargement
  maybe due to consistent lymph adenopathy. They can
  also get multiple lymph epithelial cysts.




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           SALIVARY GLAND TUMORS
Moving into a wider topic, salivary gland tumors, I will first
talk about it general, and then we will talk about some
examples.

Salivary gland tumors in general they are not common,
there is geographical variation. And tumors of major glands
more common than minor tumors. The possibility of tumors
in minor salivary glands is about15-20%. In major glands
tumors, parotid tumors comprise around 90% of the tumors.
Because the parotid gland occupy the most, it’s a large
gland.

When we look at minor gland tumors alone, 55% (more
than half) affect the palate, 20% upper labial glands. So if
you are talking about minor gland tumors you expect to find
it on the upper posterior or anywhere where we have
salivary glands.

What about the sublingual glands and the lower lip? These
are rare tumors. Now when you look at malignant and
benign, the proportion of malignant tumors in minor glands
is higher than benign. But in major glands it’s the opposite.
Also remember that its like the jaw in mandible remember
stafne’s bone cavity? And also odontogenic cysts can give
rise to entrapped salivary tissue which give rise surprisingly
to salivary gland tumors.




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         CLASSIFICATION OF GLANDS

First adenomas which are benign, then adenocarcinomas
which are malignant.




Salivary glands they do have other tissues in them, they
have muscular tissues, they can get intra parotid
hemangiomas. But now we are talking about the tumors of
salivary gland origin, not muscular or fat origin.

These are not all the tumors that affect salivary glands but
we selected the types that are common.




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           PLEOMORPHIC ADENOMA

Its also known as the mixed tumor. This is the most
common salivary gland tumor. Its found most of the time in
parotid, 60-65% of parotid tumors are pleomorphic tumors.
Around 45% of minor gland tumors are mixed tumors.
7% of these tumors originate in minor glands, especially
palatal. Usually it tends to effect old age and females.
Usually it is a solitary mass, and the recurrences may be
multifocal.

The example in the palate, remember from histology the
mass is in the junction between soft and hard palate
posteriorly. The patients might seek treatment when they get
hurt or they wait and they think that it will go away after
sometime.


        HISTOPATHOLOGIC FEATURES

Why do they call it pleomorphic? The tumor is
characterized with a variety of Histopathological features.
They have sheets myoepithelial origin or composed of cells
of epithelial. Sometimes they secrete a material like mucus,
so they call it chondroid appearance. They call it mixed
because initially they thought we have epithelial and
mesenchymal but now they found that epithelial is the main
background.

What happens in these tumors is that they proliferate or get
outgrowth. Sometimes the capsule is not really perforated.
The surgeon will try to be conservative especially with the
parotid tumor, because we have the facial nerve. They


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might not excise it with a margin, or they don’t see whats
inside so they just cut a little and they end up leaving a
small lobule inside and this is one of the reasons why we
get recurrence.

The outgrowths are not separate from the main tumor. In
constricted areas you might think it’s a separate lobule but
its not. Again there is a lot of mucous, chondroid
appearance, ductal formation, myoepithelial spread sheets
and a lot of other variation.

Myoepithelial cells take one of two forms, either they are
spindle shape (usually shape) or they are taking a rounded
shape with an eccentric nucleus. Very similar to a plasma
cell appearance, they are called (plasmacytoid cells).
Sometimes there are areas of squamous metaplasia and
keratin pearl formation.

The myxoid material inside the cells is fragile, imagine a
surgeon trying to cut it and because its so soft sometimes it
fragments easily, if remnants of this material are left in the
tumor place then we will get recurrence.

Malignant transformation can occur and usually in tumors
present for many years.


                 WARTHIN TUMOR

Its also called Papillary Cystadenoma Lymphomatosum,
although this is a long name, if you understand it you will
memorize it, its another benign tumor. Again its slow
growing, it might be multifocal. Maybe bilateral (5-10%),
first getting it on one side and a few years later on the other
side. Found in old age and its most likely found in smokers

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more than non-smokers. With studies they started thinking it
arises from residual salivary duct epithelium entrapped
within lymph nodes, which happens during development.


The gross appearance, when they took it out they found it
has these irregular cystic spaces and there is mucoid
material. The lining of the cysts has small projections that
represent the papillary structures found within the lumen.

It’s a cystic adenoma; any benign tumor containing cysts is
called cystic adenoma.


         HISTOPATHOLOGIC FEATURE

Multiple, irregular cystic spaces containing mucoid material
separated by papillary projections of tumor tissue. Why do
they call it Lymphomatosum? Its because the tumor
develops within lymph nodes, the stroma is occupied by
normal looking lymphoid tissue. The epithelial lining
consists of double layer columnar cells. These cells have an
eosinophilic granular cytoplasm. This appearance
resembles oncocytes.

Oncocytes : They are cells in glands that tend to
accumulate a lot of mitochondria.

These oncocytes line the papillary projections. Treatment is
conservative and it has an excellent prognosis.




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              BASAL CELL ADENOMA

The name again comes from the appearance, basal cell if
you look at the basal cell layer, it has small cells they are
arranged in a cord like structure. The stroma in between
them is dense connective tissue. It happens in advanced
age. 70% of it occurs in parotid and 20% in upper lip. It’s a
monomorphic adenoma.

It is well encapsulated, we can remove it easily and totally
without any recurrence, so it’s a very good prognosis.

We already talked about oncocytic cells; we have now a
tumor that completely involves oncocytic cells. We call it
oncocytoma.


                    ONCOCYTOMA

It’s a benign tumor. It’s a rare tumor. Usually arises in
parotid. Occurs in people older than 60 years old. Its
surrounded by a thin capsule and consists of oncocytes;
large cells with granular eosinophilic cytoplasm rich in
mitochondria.

For the differential diagnosis, its oncocytic hyperplasia. As I
said in old age some people tends to get oncocytes in
salivary glands, if they are proliferative its called oncocytic
hyperplasia and if they are scattered all over the gland we
call it oncocytosis.




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           CANALICULAR ADENOMA
Lesion that occurs in the upper lip, upper lip tumors tend to
be benign because most of them are canalicular adenomas
or basal cell adenoma. Why is it called canalicular?
Because it tend to have interconnecting canalicular (small
ducts) formation and it contains a lot of vascularity.
Although this tumor is benign they tend to call it multifocal
which means its not encapsulated in one spot. Again we
can see multiple microscopic foci this does not mean
malignancy! It doesn’t represent invasive growth.


               DUCTAL PAPILLOMA

Sometimes the lining of the ductal structure can have small
papilloma, when they examined it they found a tumor.
There is subtypes and we are not going to discuss them
because they are really rare. But I want you to understand
what we mean by ductal papilloma.



Moving into malignant salivary gland tumors, relatively they
are uncommon. They represent 1% or less of all body
malignancies, and 5% of head and neck malignancies. Most
frequently occur in major glands, especially parotid.
However, ratio of malignant to benign in minor glands is
higher than in major glands.




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      MUCOEPIDERMOID CARCINOMA

They represent 10% of all salivary gland tumors. Most of
them arising in parotid gland. In minor glands mostly arising
in the palate. The incidence is younger than benign tumor,
mostly happening in 4th & 5th decades.

Tumors, which have cysts, filled with mucinous secretions
they look kind of bluish in colour. They are called
mucoepidermoid cells because they have two types of cells;
epidermoid and mucous cells (they are large and pale).
Epidermoid meaning looks like squamous cells, and the
third type of cells is called the intermediate cells.

This tumor is known for its biological variant behavior. We
have high grade tumor cells and low grade tumor cells.
How do we classify as such? Based on the components of
the cells, based on the anaplastic appearance and other
types of features of malignancy i.e number of mitotic cells.

In low grade we have:

  o Well-differentiated.
  o Large number of Mucous and epidermoid cells.
  o No cellular pleomorphism. And although it’s a
    malignant tumor we don’t find a big number of mitotic
    figures.
  o Often cystic, cysts being lined by mucus-secreting
    cells.
  o Epidermoid cells present in strands or clumps, may
    show keratinization.
  o Rupture of mucin-containing cysts may lead to
    inflammation.



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In high grade we have:

   o   Poorly differentiation
   o   Epidermoid and intermediate cells predominate.
   o   Nuclear & cellular pleomorphism and atypia.
   o   Cystic spaces not prominent.
   o    Differentiation from SCC may be difficult.
   o   Ill-defined and highly infiltrative.

                     The doctor reffered to a photo and said
                     that they do a PAS stain to find the
 The doctor kept
showing pictures     nucleas inside the cells.
 but I didn’t have   Low grade tumors rarely metastasize and
them in the slides   the behavior cannot be accurately
    available!
                     predicted from Histopathological studies.
                     Overall 5-year survival rate is 70%.

The low grade tumors 5-year survival rate of 95%, local
recurrence less than10%.And in high grade tumors 5-year
survival rate is of 30-40% and the local recurrence 80%.


               ACINIC CELL CARCINOMA

The word acinic comes from acini, it is an uncommon
tumor. The dr. showed a picture with a patient that has
malignancy, you expect to see pain, ulceration and other
causes. This tumor particularly has a very good prognosis
with 80-100% 5 year survival rates for well-differentiated
tumors, and 65% for poorly differentiated ones.

The cells don’t grow in organized they still resemble acinus.
The immune system tries to defend the body from these
cells and it attacks it.



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        ADENOID CYSTIC CARCINOMA

Again it can occur in both minor and major glands, more
common in Middle-aged & elderly. Up to 30% of minor
salivary gland tumors, but only 6% of parotid tumors. It is
slowly enlarging initially like pleomorphic adenoma, but
pain and ulceration are much more common. Long term
prognosis is very fatal.

This tumor tends to invade around the nerve and then
closes on the nerve so it causes Neurological
manifestations, which causes pain and in parotid tumors
may present with facial palsy.

We have microcytic spaces and it has a cribriform pattern.
Also called swiss cheese pattern.




The doctor showed a picture of a tumor infiltrating around
the nerve. Excising it will be hard and it might dislocate to
another place causing a recurrence.




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In some cases they can try radiotherapy if excising didn’t
work. It might cause initial resolution but not permanent
clearance.

5 years survival rates for parotid tumors are 75% but
after10-year rates are dropped to 40% and after 20-year are
its less than15%. It depends on whether the tumor has been
detected early or late. The tubular types have better
prognosis than solid type. Also prognosis is less favorable in
minor glands.


 CARCINOMA ARISING IN PLEOMORPHIC
                      ADENONMA

I talked earlier about pleomorphic adenoma, if its left
untreated for long time it might end up with focus of
malignancy. That’s when we call it carcinoma ex
pleomorphic adenoma, why? Because we have previous
evidence it was benign and then turned malignant.

If this malignancy is still within the tumor capsule, it might
get a good prognosis, but if it infiltrated surrounding tissue
then the prognosis is bad.

What type of carcinoma do we get? It can be ANY salivary
gland malignancy. Notice there will be pleomorphisim and
cells with high mitotic rates.

Polymorphous Low Grade Adenocarcinoma occurs almost
exclusively in minor glands. It has a good prognosis. Most
of them arise in the palate. It has an unpredictable
potential to metastasize in 15% of cases.



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I don’t want you to memorize all this just read them, know
why they are called polymorphous, sometimes its sheets,
sometimes its in a cribriform pattern, tubular, papillary.
Its differential diagnosis can be adenoid cystic carcinoma as
both show perineural invasion.



Other salivary gland carcinoma we will not discuss but you
                        	
  
might know the names: Epithelial myoepithelial carcinoma,
Basal cell adenocarcinoma, Adenocarcinoma.

Lastly we will discuss what occurs in aging, when they
studied parotid glands, they found that there is reduction in
weight of parotid and submandibular glands related to
atrophy of secretory tissue & replacement by fibrofatty
tissue. Similar changes in labial minor glands.


Old people they wont get xerostomia, but when they take
medicine it decreases salivary flow. There will also be
oncocytic change in ductal epithelium and reduction in
flow rate in submandibular gland.



                               Done by:
                 Nadine AL Homoud




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