PathWiki: Slide 3

Normal Histological Slide of Cervix

Pathological Cervix

Slide Description: This is a low power view of the squamo-columnar junction of the cervix. Here, you can clearly see the marked basophilic staining of the undifferentiated cells, and their extension all the way to the surface. This is also called carcinoma-in-situ because it is still confined to the epithelium and not infiltrated beyond the basement membrane.

Identify:

Squamo-Columnar Junction of the Cervix. Carcinoma-in-situ.

Slide Findings:

To the left of the slide is the “marked basophilic” staining of the undifferentiated cells from the basement membrane to the surface of the lumen. This area is usually stratified squamous epithelium, but in this picture the cells have become hyperchromtic and pleomorphic (dysplasia). This is referred to as carcinoma-in-situ because mitosis occurs at all levels of the epithelium (not just basal layer) and doesn’t extend “past” the basement membrane. This is a pre-invasive stage of cancer. 100% curable at this stage. Could take 10 to 15 years to become malignant.

Q1. Name other sites where you can find squamous metaplasia and dysplasia.

Trachea and Bronchi: become stratified squamous epithelial (from normal ciliated columnar cells). This is known as metaplasiaand is usually due to some kind of an insult e.g. Vit A deficiency or through smoking. This can proceed to dysplasia of the cells demarcated by pleomorphism and hyperchromatism.

Lower esophagus: change from stratified squamous to columnar epithelium due to an insult such as acid reflux disease (Barret’s Metaplasia).

Q2. What is Schiller’s Test?

A solution of iodine to stain the cervix in which normal areas will take up the iodine because of “glycogen”, however, non-glycogen areas won’t take up the glycogen and may indicated a site of early carcinoma.

Q3. Define pleomorphism and hyperchromasia.

Pleomorphism is marked variation in size and shape of either the nuclei or the cell itself. Hyperchromasia is the increased staining capacity of the nuclei (Blue=bad) because of increased chromatin in the cell nuclei.

Morphology:

Basophillic staining of undifferentiated cells from basement membrane. Notice hyperchromatic cells (hyperstaining due to increased chromatin) and pleomorphic cells (exhibiting disorganized cellular architecture).

Disease:

Early Cervical Cancer

Etiology (main):

- Early age at first intercourse

- Multiple sexual partners

- A male partner with multiple previous sexual partners

- Persistent infection by "high-risk" papillomaviruses

Pathogenic mechanism: There is great evidence strongly linking the sexual transmission of a causative agent (in this case HPV) to cervical carcinoma. HPV types 16 and 18 have genes that can integrate into our cellular genome. They encode for proteins that have the ability to block our tumor surpressor genes TP53 and RB1. In certain epithelial cells this can activate cell cycle-related genes such as cyclin E, thus causing uncontrolled cellular proliferation. Although many women harbor these viruses, only a few develop cancer,meaning that other factors must influence cancer risk. Among the other well-defined risk factors are cigarette smoking and exogenous or endogenous immunodeficiency e.g. five-fold increase of in-situ carcinoma in women that have HIV.

Structural changes (specific, gross, and micro):

Cytologic examination can detect CIN (SIL) long before any abnormality can be seen grossly.

- Mild dysplasia, this lesion is characterized by koilocytotic changes (perinuclear vacuolization) mostly in the bottom layers of the epithelium.

- Moderate Dysplasia, if the condition progresses without treatment then we see variation in cell and nuclear size but still normal looking well differentiated cells on the superficial layer.

- Severe dysplasia and carcinoma in situ, exhibits variation in cell and nuclear size, disorderly orientation of the cells, and normal or abnormal mitoses; these changes affect virtually all layers of the epithelium and are characterized by loss of maturation. Differentiation of surface cells and koilocytotic changes have usually disappeared.

Early Dysplasia where there is atypical variations on the cellular and nuclear level affecting the lower half of the epithelium.

 

Late Dysplasia exhibits total loss of maturation affecting the entire epithelium.

 

To the left of center is a normal mature squamous cell. Grouped around it are the atypical cells with enlarged hyperchromatic nuclei and less cytoplasm; hence they are smaller.

 

High-grade SIL are smaller, have less cytoplasm with large atypical nuclei, and have a corresponding increase in the nuclear-cytoplasmic ratio. Note the normal squamous cell at the top.

Are there any other sites of involvement in the body? N/A

Are there any other diseases where similar changes can be seen? Other cancers will exhibit the same changes in general cell structure.

Signs / Symptoms: Early stage cervical cancer may have no symptoms at all. These symptoms of cervical cancer do not usually appear unitl the cancer has invaded nearby tissue. Symptoms are:

Abnormal bleeding that may start and stop between regular menstrual periods

Bleeding after sexual intercourse

Bleeding after douching, or a pelvic exam

Menstrual bleeding may last longer and be heavier than usual

Bleeding after menopause

Increased vaginal discharge

Investigations (confirmation / gauge extent):

Precancerous and cancerous cells can be detected through a pap smear. A pap smear is done by taking a smaple of the outer cells of the cervix. This is done with a tiny brush run across the cervix and the sample examined under a microscope. If abnormal cells are detected a colopscopy is done. A vinegar-like solution is applied to the cervix and then it is looked at with a colposcope. Abnormal cells will turn a different color than normal cells.

Another test is a biopsy. There are two types of biopsy done to detect cervical cancer. One is called LEEP or loop electrosurgical excision procedure. In this procedure a local anesthesia is applied to the cervix and then the doctor will slice off a small round portion of the cervix with an electric wire loop. The other procedure is called endocervical curettage (ECC), the doctor uses a small, spoon-shaped instrument to scrape tissue from inside the cervical opening. Both procedures can cause some bleeding, discharge and menstrual like cramping.

Are there any other diseases you have studied where such tests can be positive?

No, these tests seem highly specific to this type of cancer.

Course of disease progress (complications, monitoring, outcome):

Preinvasive stage: diagnosis is usually done in this phase by methods listed above, more advanced cases of cervical cancer are invariably seen in women who either have never had a Pap smear or have waited many years since the prior smear. This is where such tumors may be symptomatic (listed above). In general upon cancer there is a five year survival time period given, with percentage of survival decreasing with each year.

Highlight 3 important points:

- Risk factors

- Cells have increased nucleus to cytoplasmic ratio (note normal is 1:4, 1:5)

- that prevention has been the major determinant in the prevelance of cervical cancer.

Vignette

A mother of five comes to you for her regular monthly check-up...you conduct a regular paps smear and find some "different looking cells"..what do you do next?