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New Treatments for  Cancer of the Cervix

Here is the case of a 28-year-old female w ho presented with a very large ulcerating and necrotic mass on the cervix. The preoperative diagnosis from the clinician was cancer of the cervix, cervix cancer, cervical cancer. On biopsy, there was an area of ulceration, then endocervical stroma with lots of congested big vessels. On higher power, the area of ulceration showed numerous acute and chronic inflammatory cells. In these areas of ulceration were very large multinucleated cells with rather intranuclear ground glass-type inclusions. These are very characteristic of the herpes virus. This was a case of herpes cervicitis. One of the reasons I chose to bring this case to you today is because it is an example of a benign inflammatory process of the cervix and because it clinically, as in this case, can be mistaken for carcinoma. The herpes virus received considerable attention many years ago.

The second case is a 30-year-old lady who went to her gynecologist for a routine checkup and on Pap. smear. smear she was shown to have atypical cells, most likely dysplastic in nature. Thereafter, a biopsy was performed. Normal squamous epithelium of the cervix is a single basal cell layer, which is very orderly and organized. The cells in the basal cell layer are small and have a scant amount of cytoplasm. If one is going to see mitoses, normally it will be seen in the basal cell layer. As the cells mature, the nuclei get smaller and there becomes more abundant cytoplasm with increasing amounts of glycogen. At the top, the nuclei are very small and slightly spindle shaped. This is the underlying endocervical stroma.

The WHO and the International Society of Gynecologic Pathologists have a three-tier system - Mild dysplasia to severe dysplasia. Bethesda has adopted a two-tier grading system - the mild dysplasias are called the low-grade squamous intraepithelial lesions and the higher-grade cells will basically incorporate both the moderate dysplasia and the severe dysplasia. The grading of the cervical intraepithelial neoplasia cells is basically based on the proportion of epithelium occupied by those very basaloid, undifferentiated cells - the cells at the base.

CIN-I, or low-grade cells, with marked HPV effect.

The next case was in her 30s. The patient went to her gynecologist and had a cone excisional biopsy for the workup of previously diagnosed CIN. On cone excisional biopsy just on lower power, one could see some of these endocervical glands had a fair degree of architectural atypia or complexity in that they had some budding or protuberances. On higher power, one could see an abrupt change in the endocervical glands from normal endocervical glandular epithelium to neoplastic epithelium. The normal endocervical glandular epithelium has a very small basally-locally nucleus and abundant cytoplasm with mucin. In addition, normal endocervical glands should very rarely have mitotic figures. Neoplastic epithelium is very different; it has very crowded, pseudostratified cells, the nuclei are very cigar-shaped, elongated and hyperchromatic and often you may be mitotic activity. The endocervical stroma surrounding this appears fairly normal, which is very important, because this lesion represents adenocarcinoma in situ. In situ is retained within the basement membrane and there is no invasion.

Another lesion that can be mistaken for dysplasia is squamous metaplasia, which we often see in biopsy specimens. There is normal endocervical glandular epithelium. What happens with squamous metaplasia is that the normal endocervical glandular epithelium - mucin producing columnar epithelium - becomes replaced by squamous epithelium. One can on lower power see a bit of disorganization but it can be mistaken for dysplasia. However, on high power, one can see normal endocervical glandular epithelium and squamous epithelium.

The next case is a 50-year-old female who presented with vaginal bleeding. The gynecologist noted on physical examination that the cervix appeared slightly thickened and a biopsy was performed. The biopsy revealed, in the underlying stroma, very irregular complex glandular structures infiltrating deeply into the cervical stroma; they were not superficial at all. The normal endocervical gland level or depth is usually about 5 to 7 mm below the base of the epithelium. In our case, they infiltrated deeply and were very complex. Some of them had out-pouchings.

There are seven histologic subtypes of invasive adenocarcinoma. The first is the mucinous adenocarcinoma, which the above case actually represents. There was very little mucin, but in some areas, one could appreciate mucin. Mucinous adenocarcinomas can be divided into three histologic subtypes - the endocervical subtype, which basically has cells.

The second most common is the endometrioid adenocarcinomas and those look very similar to the endometrial adenocarcinomas. Those comprise about thirty percent of cases.

The third most common is the clear cell adenocarcinomas, which are strongly associated with DES exposure. They are seen in young women who have had previous in utero exposure to DES. However, people who have not been exposed to DES can also develop clear cell adenocarcinoma. The cytoplasm is clear because it contains glycogen as opposed to mucin.

Minimal deviation adenocarcinomas are so-called because they actually lack the cytologic features of malignancy. They look cytologically extremely benign; however, they infiltrate the stroma way below the normal level of the endocervical glands. They infiltrate beyond 7 mm. They are very difficult to pick up. One really needs a deep biopsy to pick them up.

The fifth serous subtype is serous adenocarcinoma, similar to the endometrioid; these are rare, but you may see it in the cervix.

The mesonephric adenocarcinomas are derived from the mesonephric remnants which are basically seen in the lateral wall of the cervix.

The last is the well-differentiated villoglandular adenocarcinomas. These adenocarcinomas have a very good prognosis and they usually occur in younger women. Most of these adenocarcinomas occur in about the 50s. The well-differentiated adenocarcinoma usually occurs in a woman at the median age of about 37. They have a very good prognosis.

The next case is a lady in her 50s who also presents with vaginal bleeding. On physical examination, the gynecologist noted a mass in the cervix. A biopsy was performed, revealing squamous cell carcinoma and hysterectomy was therefore performed. On examination of the uterus, on higher power, one can see that the cervix is entirely replaced by a polypoid, irregular mass. On closer exam, one can see infiltrating nests of tumor cells. The tumor is composed of these anastomosing cords and tongues of neoplastic squamous epithelium. The stroma is very reactive. The overlying squamous epithelium shows severe dysplasia or carcinoma in situ.

Intercellular bridges are also evidence of squamous differentiation.

I'd like to talk at this point about the three different grades. Grade 1 squamous cell carcinoma; grade 2 squamous cell carcinoma; and Grade 3 squamous cell carcinoma. How do we grade them? Basically, grade 1, or well-differentiated squamous cell carcinomas, look very similar to the normal squamous epithelium; they have keratin pearls, they have intercellular bridges.

At this point, I would also like to talk about the variety of squamous cell carcinomas. There are actually six types. The first one which is very important for you to remember is the microinvasive squamous cell carcinoma of the cervix.

The second type, obviously the most common, is an invasive squamous cell carcinoma. The third one is what is known as a verrucous carcinoma . Verrucous carcinoma actually has a very good prognosis; it recurs, but not metastasize. The fourth one is called a warty carcinoma. The warty carcinomas have marked HPV-like effects but also have malignant cytology. This has a prognosis in between the invasive squamous cell carcinomas and verrucous carcinomas.

I've shown you a case of adenocarcinoma of the cervix, squamous cell carcinoma of the cervix and we have talked about the different subtypes. There are other epithelial tumors of the cervix - there is adenocystic, adenoid basal, glassy cell and a lot of histologic subtypes. One of the subtypes I'd like to mention is a tumor that can be mistaken or confused with a poorly-differentiated squamous cell carcinoma. It is quite important to distinguish the two