Stem cells and differentiation in human prostate cancer

Human prostate epithelium consists of two cell layers within which three cell types are recognized: basal, luminal and neuroendocrine cells, each of which has many phenotypic variants. Prostate cancers contain cells with similar phenotypes, but the patterns of growth and differentiation are altered to varying extents within each cancer.

An important concept is that the degree of differentiation is inversely proportional to the capacity for cell division. In normal prostate epithelial cells, there is a relatively strict division of labor, and cells that produce prostate-specific antigen (PSA) are unlikely to be proliferative. In contrast, one of the characteristics of prostate cancer is the blurring of this distinction.

In order to understand prostate cancer cell differentiation, it is first necessary to understand normal prostate epithelial cell growth and differentiation. Many studies of normal and abnormal prostate tissue derived from fetuses, boys, young men and older men have been published. However, few definitive conclusions have been reached.

The aim of this review is to summarize the literature describing the patterns of differentiation seen in human normal prostate epithelium and consider how these are altered in prostate cancer.

Prostate normal epithelial cell lineages

In the normal prostate epithelium, a nearly complete layer of basal, relatively undifferentiated cells is the progenitor of the luminal layer of columnar PSA-secreting cells1-3. Interspersed amongst these cells are scattered individual or small groups of neuroendocrine cells. It is thought that the stem cells reside in the basal layer, where the majority of cell division occurs.

A number of interrelated questions arise, including:

(1) What is the sequence of phenotypes during prostate epithelial cell differentiation?
(2) Is there, in some areas, a cell layer between the basal cells and the secretory cells?
(3) What is the phenotype of the cells transiting between the basal and luminal layers?
(4) Does prostate epithelium contain some cells with characteristics of both basal and luminal cells?
(5) What is the origin of the neuroendocrine cells?
(6) Is stem cell division monodirectional or can the prostate epithelial stem cell give rise to two populations of transit amplifying cells, one of which divides to give basal cells and one to luminal cells?
(7) What are the differences in the patterns of differentiation between the transition, central and peripheral zones of the human prostate?
(8) Which cell type(s) give rise to prostate cancer?

Study of these questions has been facilitated by the use of a number of markers, particularly cytokeratins (CKs). The classical lineage markers are CK5/14 (and p63) for basal cells, CK8/18 (and PSA, nuclear androgen receptor (AR), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PSAP)) for luminal cells and chromogranin A or CD56 for neuroendocrine cells. However, extending the range of markers studied has demonstrated that there are many other phenotypes present in both the basal and luminal layers.

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The histology of cervix cancer

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.

National cancer institute

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.

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

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.

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.

Squamous metaplasia

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.

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.

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.

Cervical cancer. Conclusion

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.

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.

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.

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