Cancer information Cancer treatment

The histology of cervix cancer

Canadian Health — Fri, 25 Dec 2009 10:08:22 +0000

The histology of cervix cancer is by and large, about 90% at least, squamous lesions. The other 10% are adenocarcinomas arising in the endocervical canal. Really for purposes of treatment and staging, we treat all the same with one little exception so that the pathologist will subdivide for you the biopsy. Saying this is a squamous cell lesion, it’s a large cell non-keratinizing and that really is going to be treated the same, whether it’s keratinizing or non-keratinizing. The one exception that we find on rare occasion is this small cell carcinoma of the cervix, with neuroendocrine elements. An exceedingly rare lesion. Sort of defies the usual spread patterns and prognosis in that it oftentimes hematogenously spreads and spreads widely despite the fact that it appears to be an early lesion, managed by surgery or radiation therapy. The role of chemotherapy in this group of patients is debated. I think most of us would probably add chemotherapy to that patient, even if she had early stage disease. But it’s such a rare lesion we don’t have clear cut clinical evidence of what’s the right thing to do.
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In staging the patients with cervix cancer, the spread patterns are fairly monotonous and routine. Local spread to the vagina, the perimetria, the tissue next to the cervix and invading the cervical stroma are the initial routes of spread. From there into lymphatics and the lymphatics are again in a step-wise fashion, have to metastasize to pelvic lymph nodes before they will go to periaortic or common ileac lymph nodes. It’s a fairly step-wise progression. Hematogenous metastases can be seen in liver and lung and bone. Usually those patients have very advanced local disease, stage III disease, spreading sidewall to sidewall.
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The staging system that we use and have modified over the years is a clinical staging system, rather than a surgical staging system that we use for endometrial cancer or for ovarian cancer. Cervix cancer is a clinically staged disease because most patients won’t undergo surgery as part of their treatment. They’ll be treated with radiation therapy and chemotherapy now, in most cases. We want to determine the extent of the disease on clinical examination, including a good pelvic examination. Cystoscopy and proctoscopy to evaluate whether there is any invasion anteriorly or posteriorly into the bladder and rectum are reasonable. Surgical staging on the other hand, with second look laparotomy in ovarian cancer, is not considered standard of care. It does fit into some of the clinical protocols that are ongoing or is required that the patient have a lymph node dissection prior to entering a randomized trial but certainly would not be considered standard of care. CT scan, on the other hand, is probably the single most effective test for staging, looking at adenopathy, looking at the liver, looking at the potential for obstructive ureters. So a CAT scan is an important part of that patient’s initial work-up. Stage I disease is disease clinically thought to be confined to the cervix. It’s subdivided by depth of invasion. This requires a conization of the cervix to get a big sample of the cervix to evaluate the depth of invasion. And it’s also related to the size of the primary lesion, if it’s a gross lesion less than or greater than 4 cm in diameter. Stage II is just sort of the next concentric ring of spread locally, into the vagina and the perimetria and the tissue beside the cervix. Stage III, lower vagina or out into the pelvic side-wall. Again, sidewall involvement is determined by a gynecologist on pelvic examination or if the patient has an obstructed ureter. Then stage IVa is rectal or bladder involvement, and IVb would be distant metastases such as lung or liver metastases.

Cancer of the Cervix, Vulva, Vagina

Canadian Health — Wed, 23 Dec 2009 17:26:19 +0000

Herpes simplex virus infections increase that woman’s risk, women that are HIV positive are at much higher risk, those that are smokers, and those that are immunosuppressed or renal transplant patients for example that have an HPV infection are at much higher risk to go on to develop cervical cancer. There are at least 10-20 million women with HPV infections and probably you can equate that to the same number of men out there. Of those 20 million, only about 1.2 million go on to develop these preinvasive lesions, cervical dysplasia, and only about 13,000 a year develop invasive cancer. Because a patient has HPV show up on a Pap smear with cytologic changes associated with HPV, or has mild dysplasia caused by HPV, doesn’t mean that she is going to go on to develop invasive cancer. Unfortunately we don’t have an antiviral agent or an HPV vaccine yet available. So to identify which patients are at high risk and low risk is somewhat of a clinical challenge to the gynecologist and the GYN-oncologist.

Most patients with invasive cervix cancer we would hope would be picked up with an abnormal Pap smear, appropriately referred to a gynecologist. The patient would undergo colposcopy, which is nothing more than a 15 power dissecting binocular microscope to look at the cervix, identify the lesion, biopsy the invasive lesion and go on to stage and treat. Cold knife conization is a larger biopsy. Yet unfortunately most patients that we see today still have gross lesions that Papanicolaou was trying to prevent or avoid, but have gross lesions that can be directly biopsied by the gynecologist. Identifying that patient is a common problem in the United States yet today.
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The symptoms associated with cervix cancer is vaginal bleeding. It is one of the classic symptoms, although not oftentimes volunteered in my experience, but if you ask the patient, yes she has had bleeding after intercourse; it stops after a day or so and doesn’t reoccur until she has intercourse again. As the cervix cancer progresses you can get pelvic pain, obstruction of the lymphatics and lead to lymphedema or obstruction of ureters and ultimately uremia. But the most common early symptom is abnormal bleeding, and again managing that patient by telephone is inappropriate. She needs to be seen, a Pap smear obtained and examined.

Cervical cancer. Conclusion

Canadian Health — Fri, 18 Dec 2009 15:30:31 +0000

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 and they look like squamous epithelium. The poorly-differentiated, or grade 3, squamous cell carcinomas really don’t have many features of squamous epithelium and one has to look to see if this is a squamous cell carcinoma or adenocarcinoma . This is the difference between a well-differentiated and poorly-differentiated carcinoma. Again, the grading system has conflicting studies as to whether this portends diagnosis and it appears most likely that the stage is obviously the most important prognostic factor.
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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. This is basically defined as a tumor which invades the stroma less than 3 mm below the base of the epithelium and which has no lymphatic or vascular space invasion. If one keeps strict criteria, these tumors actually do not metastasize and do not recur, if they keep to the criteria of less than 3 mm and no vascular or lymphatic invasion.

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. Transitional cell carcinomas are extremely rare; they look like transitional epithelium. They are similar prognostically to the invasive squamous cell carcinomas but they may have late recurrences. Lastly is the lymphoepithelioma-like carcinoma, which is a carcinoma which is associated with a strong lymphocytic response. While you don’t have to know the difference between the different types histologically, some of them have a little different prognosis.
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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 because this is an extremely aggressive tumor. These tumors are very cellular, they have sheets of cells, they do not have any gland formation and the cells are small with scant cytoplasm. They have sort-of stippled chromatin and numerous mitotic figures. Small cell carcinoma of the cervix is another subtype worth mentioning. If one does neuroendocrine markers or immunohistochemistry, these are actually neuroendocrine positive. Neuroendocrine tumors are like oat cell carcinoma of the lung. Again, they can be confused with poorly-differentiated squamous cell carcinoma, especially the more small cell type. They are extremely aggressive. These patients present with a barrel-shaped cervix. They are very infiltrative tumors. Clinically, although uncommon, they may have ectopic ACTH production.

Villoglandular adenocarcinomas

Canadian Health — Tue, 15 Dec 2009 14:17:33 +0000

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.
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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. The invasiveness of this tumor is clearly seen in the very irregular, shaggy and tongue-like contours. The stromal reaction is pronounced as well with inflammatory cells and a more desmoplastic, spindly-type reaction. This is the reaction the stroma has when there is an invasive tumor. On higher power, one can see that the neoplastic epithelium consists of very pleomorphic cells, some of them multinucleated with numerous mitoses and some evidence of individual cell keratinization. A keratin pearl is when keratin is deposited in a concentric whirl in the center of neoplastic squamous epithelium. This is evidence that this is a squamous differentiation, because it has a keratin pearl. The WHO have classified squamous cell carcinomas as to whether they are keratinizing or non-keratinizing. The keratinizing tumors have these keratin pearls; the non-keratinizing do not. As to prognostic significance, there are essentially very conflicting studies as to whether this really has any prognostic significance.
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Intercellular bridges are also evidence of squamous differentiation.

Endometrioid adenocarcinomas

Canadian Health — Fri, 11 Dec 2009 13:37:29 +0000

The second most common is the endometrioid adenocarcinomas and those look very similar to the endometrial adenocarcinomas. Those comprise about thirty percent of cases.
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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. They are strongly associated with Peutz-Jeghers syndrome. In addition, if there is an adenocarcinoma that is going to be associated with an ovarian carcinoma, this is the adenocarcinoma which is often associated with ovarian adenocarcinoma. Ovarian adenocarcinomas tend to be a mucinous type or the six-core tumor type with annular tubules. Minimal deviation adenocarcinomas are very rare.

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.

Squamous metaplasia

Canadian Health — Wed, 09 Dec 2009 16:59:11 +0000

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 cells are very organized, there is no cytologic atypia, there are no mitoses, they have abundant eosinophilic cytoplasm. All these features say that this is not dysplasia; this is squamous metaplasia. This is very common in biopsy specimens. Our case represents cervical adenocarcinoma in situ. There are no precursor lesions, no morphologic biologic precursor lesions identified. The mean age is around 39 to 46 years. Most of these are associated with the human papilloma virus, in particular human papilloma virus 18, similar to severe dysplasia. The prevalence is less than the SILs or the CINs. The natural history is not as well documented or known as the SILs.
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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. In other areas, they had what is known as a cribriform arrangement, where there are multiple glands within glands and multiple lumina. In addition, the stroma was quite reactive and there were numerous inflammatory cells, with a somewhat desmoplastic appearance. Cytologically, besides architecturally being very malignant, cytologically it was extremely malignant. Numerous mitoses were seen and one should not see normal endocervical glands; there were papillary enfoldings, which should not be seen, and the cells had prominent, angry-appearing nucleoli, vesicular-looking chromatin and large nuclei. This is an example of an invasive adenocarcinoma as opposed to adenocarcinoma in situ. It is invasive, it has malignant cytology, the stromal reaction shows that it is invasive and it is deeply infiltrative.
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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 similar to the normal endocervical glandular epithelium; the intestinal subtype, where you actually see goblet cells, similar to what is seen in the intestine; and the signet-ring subtype. These three types are similar in prognosis. The mucinous adenocarcinoma is the most common.

Low-grade cells with marked HPV effect.

Canadian Health — Mon, 07 Dec 2009 19:24:04 +0000

CIN-I, or low-grade cells, with marked HPV effect.
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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. By no invasion, I mean that there is no endocervical reaction and the abrupt change is very characteristic of adenocarcinoma in situ thirdly, the depth of glands are not beyond the level of normal endocervical glands. Adenocarcinoma in situ is very characteristic for this. In other places in this patient there was CIN-III, severe dysplasia. Here, the full thickness of the epithelium is occupied by small, basaloid, undifferentiated cells with a lot of nuclear crowding, pleomorphism and disorganization and the presence of mitotic figures. So this is an example of severe dysplasia, or carcinoma in situ. Severe dysplasia involving the superficial endocervical glands may be mistaken for invasive carcinoma, because it appears to go into the underlying stroma. I do not call this invasive carcinoma is because the borders of the gland are very smooth and regular and the stroma is very normal looking and is not reactive. In invasive carcinoma, the stroma tends to be more reactive and the borders tend to be very irregular and shaggy. I would call this severe dysplasia involving an endocervical gland. The hint is the endocervical glandular epithelium.
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Cancer of the Cervix

Canadian Health — Thu, 03 Dec 2009 13:34:12 +0000

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 carcinoma. 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 in its role in the pathogenesis of cervical carcinoma. Since then, there have been numerous conflicting studies as to whether or not it does play a role. Some studies support the association of herpes cervicitis with cervical carcinoma and its precursor lesions, while other studies refute it. It appears that further studies are needed to define the role better in the pathogenesis ofo cervical carcinoma. The cervical involvement in patients with primary herpes genital lesions is usually around about ninety percent. In patients with recurrent genital herpes, involvement of the cervix is about twelve to twenty percent.
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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. Our patient’s squamous epithelial layer is very different. She had very atypical cells in the more superficial layers. The basal cell layer was slightly thickened and slightly disorganized, but not particularly so. On higher power, koilocytotic atypia was noted. There was nuclear enlargement, nuclear hyperchromasia, which means that the chromatin was very, very dark, and there was marked wrinkling and irregularity of the nuclear membrane. In addition, one could see perinuclear cytoplasmic vacuolization and in some cells, showed multinucleation. These are the cytopathic effects of the human papilloma virus. The terminology for cervical cancer precursor lesions includes two groups of thought. 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. Cheap cymbalta online. This basically reflects progressive loss of epithelial maturation. The lower third of the epithelium is occupied by these type of cells; moderate occupies the lower third to two-thirds; severe occupies two-thirds to full thickness. It is very important to note that even if the basal cell layer is orderly and you don’t have many basaloid undifferentiated cells in the lower third, but you have marked HPV effect, that is still classified as mild dysplasia with HPV effect. As you know, the precursor lesions are associated with the human papilloma virus. The low-grade lesions tend to be associated with any of the anogenital HPVs. The higher-grade lesions, however, are associated with 16, 18, 31 and 33, which is important to remember. So our patient has mild dysplasia.

Bladder cancer treatment

Canadian Health — Fri, 27 Nov 2009 17:17:49 +0000

A. Intravesical Chemotherapy: Immuno- or chemotherapeutic agents can be delivered directly into the bladder by a urethral catheter. They can be used to eradicate existing disease or to reduce the likelihood of recurrence in those who have undergone complete transurethral resection. Such therapy is more effective in the latter situation. Most agents are administered weekly for 6–12 weeks. The use of maintenance therapy after the initial induction regimen may be beneficial. Efficacy may be increased by prolonging contact time to 2 hours. Common agents include thiotepa, mitomycin, doxorubicin, and BCG, the latter being the most effective agent when compared with the others. Side effects of intravesical chemotherapy include irritative voiding symptoms and hemorrhagic cystitis. Systemic effects are rare. Patients who develop symptoms from BCG may require antituberculous therapy.
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B. Surgical Treatment: Although transurethral resection is the initial form of treatment for all bladder cancers as it is diagnostic, allows for proper staging, and will control superficial cancers, muscle infiltrating cancers will require more aggressive treatment. Partial cystectomy may be indicated in patients with solitary lesions and those with cancers in a bladder diverticulum. Radical cystectomy entails removal of the bladder, prostate, seminal vesicles, and surrounding fat and peritoneal attachments in men and in women also the uterus, cervix, urethra, anterior vaginal vault, and usually the ovaries. Bilateral pelvic lymph node dissection is performed simultaneously.

Urinary diversion can be performed using a conduit of small or large bowel. However, continent forms of diversion have been developed that avoid the necessity of an external appliance.

C. Radiotherapy: External beam radiotherapy delivered in fractions over a 6- to 8-week period is generally well tolerated, but approximately 10–15% of patients will develop bladder, bowel, or rectal complications. Unfortunately, local recurrence is common after radiotherapy (30–70%). Increasingly, radiotherapy is being combined with systemic chemotherapy in an effort to improve local and distant relapse rates.
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D. Chemotherapy: Fifteen percent of patients with newly diagnosed bladder cancer will present with metastatic disease, and 40% of those thought to have localized disease at the time of cystectomy or definitive radiotherapy will develop metastases usually within 2 years after the start of treatment. Cisplatin-based combination chemotherapy will result in partial or complete responses in 15–35% and 15–45% of patients, respectively.

Combination chemotherapy has been integrated into trials of surgery and radiotherapy. It has been used before each in an attempt to preserve the bladder and decrease recurrence rates. Alternatively, it has been employed postoperatively in patients who have undergone cystectomy and have been found to be at high risk of recurrence. In current practice, adjuvant chemotherapy when indicated—ie, when the primary tumor invades perivesical fat or adjacent organs or when lymph nodes are found to have metastatic disease—is being offered mainly to patients being treated with radical cystectomy. It is used less often for patients with unresectable disease (extension to pelvic side wall).

TNM staging system for bladder cancer.

Canadian Health — Thu, 26 Nov 2009 16:18:50 +0000

T: Primary tumor

Tx Cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ (CIS)

Ta Noninvasive papillary carcinoma

T1 Invasion into lamina propria

T2 Invasion into superficial layer of muscularis propria

T3a Invasion into deep layer of muscularis propria

T3b Invasion through serosa into perivesical fat

T4a Invasion into adjacent organs

T4b Invasion into pelvic sidewall

N: Regional lymph nodes

Nx Cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in a single lymph node £ 2 cm
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N2 Metastasis in a single lymph node > 2 cm and < 5 cm or multiple

nodes none > 5 cm

N3 Metastasis in lymph node > 5 cm

M: Distant metastasis

Mx Cannot be assessed

M0 No distant metastasis

M1 Distant metastasis present

The natural history of bladder cancer is based on two separate but related processes: tumor recurrence and progression to higher stage disease. Both are related to tumor grade and stage. At initial presentation, approximately 50–80% of bladder cancers will be superficial: Ta, Tis, T1. Lymph node metastases and progression are uncommon in such patients when they are properly treated, and survival is excellent at 81%. Patients with superficial cancers (Ta, T1) are treated with complete transurethral resection and the selective use of intravesical chemotherapy. The latter is used to prevent or delay recurrence. Patients who present with large, high-grade, recurrent Ta lesions, T1 cancers, and those with carcinoma in situ are good candidates for intravesical chemotherapy. Patients with more invasive (T2, T3) but still localized cancers are at risk of both nodal metastases and progression, and they require more aggressive surgery, irradiation, or the combination of chemotherapy and selective surgery or irradiation due to the much higher risk of progression compared to patients with lower-stage lesions. Patients with evidence of lymph node or distant metastases should undergo systemic chemotherapy initially.
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