Prostate Tumors Lecture PDF

Pathology and diagnostics P. Colombo – Pathology - Lecture 08 Tumors of the prostate 24/10/2024 – Group 35 (Savant Levra- Pozzolini) In case of potential tumors, knowing the anatomy of the prostate...

Pathology and diagnostics P. Colombo – Pathology - Lecture 08 Tumors of the prostate 24/10/2024 – Group 35 (Savant Levra- Pozzolini) In case of potential tumors, knowing the anatomy of the prostate is fundamental: Remember that the prostate can be divided in an anterior, posterior, apical and basal region. The base is directed upward near the inferior surface of the bladder. The greater part of this surface is directly continuous with the bladder wall. The apex is directed downward in contact with the superior fascia of the urogenital diaphragm. More importantly, remember that the gland can be divided into an anterior, transitional, central and peripheral zone. The peripheral zone is the traditional location of prostate adenocarcinoma, which can be located in the left lobe, in the right lobe or, more frequently in the posterior area. On the back of the gland there is the Denonvillier fascia, which is an anatomical structure used by surgeons to resect the prostate from the rectum. In the case of tumors, differently from benign prostatic hyperplasia, the cells that play a chief role are epithelial cells, particularly secretory and basal cells. In a normal gland, one can distinguish a layer of basal cells, covered by a layer of secretory cells that surround the lumen of the gland. The most common epithelial prostatic tumors are: 1) Acinar adenocarcinoma (95%). The acini are the fundamental unit of the prostate. 2) Ductal adenocarcinoma (5%). Ductal adenocarcinoma is different from acinar adenocarcinoma in that it arises in the area between the central and transitional zone, close to the urethra. In general, an adenocarcinoma of the prostate is due to the proliferation of abnormal epithelial cells. Ductal adenocarcinoma is much rarer than acinar adenocarcinoma, which is different for example from breast tumors; indeed, the most common type of breast tumor is ductal carcinoma and acinar carcinoma, called lobular carcinoma, is less frequent. 1 Epidemiology: prostate adenocarcinoma is the most common cancer in the male population in many different countries. Risk factors for prostate cancer are not only environmental, but also genetic: for example, people of African descend are more predisposed to developing a prostate cancer; even though many patients do still develop this tumor somatically. It’s important to note that prostate cancer represents 14% of tumors in the US, and among these mortality is fortunately not very high, around 5%. However, we also should note that these numbers, the number of deaths included, have not changed in about ten years; meaning that in ten years no novel therapies have been developed for prostate cancer. If you look at the graph on the right, you can notice a peak in new cases during the Nineties: this is not because of an increase in incidence, but because of the discovery of a new diagnostic method: prostate specific antigen (PSA). PSA: it’s an hormone secreted by epithelial cells, that increases in serum concentration when changes are occurring in the prostate. Particularly, it increases significantly in cases of prostate cancer; however, it can also increase in case of inflammation, infection, or physical triggers such as biking. Therefore, when PSA was discovered, it was used to perform cancer screening and diagnosis, which lead to the identification of both high risk but also low risk, small foci of adenocarcinoma, which would be clinically irrelevant. PSA is also an age related hormone. Take home message is: PSA also increases in early adenocarcinoma, which is not clinically relevant. Analizing autopsies, another aspect of prostate adenocarcinoma can be seen: autopsy based prevalence is higher for all age brackets with respect to clinical incidence. This means that there is a high incidence of low risk, not clinically significant prostatic adenocarcinoma that is not screened and then gets discovered in autopsies. Older men have higher incidence of prostate cancer. However, also at 30-39 years old there is a small risk to develop prostate adenocarcinoma. In younger patients, mesenchymal tumors of the prostate are more common instead. Risk factors: Patients who have not undergone puberty or have been castrated are not subjected to prostate cancer. Similarly, pseudohermaphrodites with a deficiency in 5-alpha-reductase (who therefore cannot convert testosterone in DHT), cannot develop prostate cancer. Incidence of primitive and metastases of prostate cancer is also decreased by surgical castration, estrogenic therapy or by using an anti-androgen therapy (anti-testosteron). Anatomical location of prostatic adenocarcinoma: most prostatic adenocarcinomas are multifocal. 75-80% of them arise in the posterior or posterolateral peripheral zone; instead, only about 13-20% arise in the transitional and periurethral zone, but these tumors often have a low grade and generally 2 have low aggressiveness. The anterior zone is interested by a lower number of prostate cancer, but maybe this can also be due to the fact that urologists do not readily provide samples from this zone. Diagnosis methods: Fine needle biopsy: gold standard for prostatic adenocarcinoma diagnosis. Tissue must be fixed with formalin at a 10:1 dilution (10 of formalin and 1 of tissue). Biopsies also need to be numbered and ordered. Transurethral section performed for BPH: this procedure can reveal in 10-16% of cases the presence of occult prostatic adenocarcinomas, mostly affecting in this case the transitional zone. Imaging: can reveal the presence of the so called ROI (region of interest) from which the biopsy will then be collected. Commonly used techniques are Ultrasound, Ultrasound overlapped with MR, or even a PET scan with contrast. The prostate can also be reconstructed in 3D. For diagnosis, clinical history (PSA levels, US information and rectal examination) and information about previous therapy are important. Particularly, it’s important to not underestimate the importance of previous therapy because, for example, radiotherapy used to cure colorectal cancer may damage and change the histological features of the prostate, and this must not be confused with a prostate adenocarcinoma. Note: fine needle aspiration should never be used, because it only provides information about the cells, not tissue organization, and prostate adenocarcinoma, differently from breast and thyroid cancer, is based on architectural features and not on cytologic features. Gross features: surgical specimens are inked and then cut into slices so that all the different zones can be evaluated together to ideally inform the surgeon. Generally, prostate adenocarcinomas are white areas, mostly in the peripheral zone and present infiltrative growth patterns within normal or hyperplastic glands. However: note that it’s not possible to identify tumors of the prostate basing exclusively on gross features. One of the reasons for this is that, because we can use PSA to diagnose 3 prostate cancer, in many cases adenocarcinomas are discovered when they are still very small, and therefore it’s difficult to identify them with our naked eyes. Prognostic markers: grading (histological differentiation), surgical margins, volume of the tumor (expressed in percentages compared to the volume of the entire gland), seminal vesicles infiltration (it can be uni or bilateral), vascular or lymphatic invasion and metastases to lymphonodes. Gleason score: Gleason score defines the histological differentiation of prostate adenocarcinomas, based on the architectural conformation of the tissue. Gleason score has been adjusted three times in the past years; originally, five patterns of growth where described, however nowadays we know that pattern 1 and pattern 2 do not exist as separate entities, but instead they are components of pattern 3. Therefore we use pattern 3 to pattern 5 to describe the histological features of prostatic adenocarcinomas. The grading method is the following: during microscopical analysis the pathologist identifies the two most represented architectural patterns within the tumor, and then sums them. For example, if in one adenocarcinoma the most represented pattern is pattern 3, and pattern four can be recognized, but is represented less, the Gleason score will be 3+4 (the most represented pattern must be written first). If a tumor only presents pattern 3, Gleason score is 3+3 (the same goes for only 4 and only 5 pattern tumors). Therefore, Gleason score can go from 6 to 10. Prognostic grade group: the fact that the lowest grade tumor is 3+3, therefore grade 6, used to confuse patients, who thought they had an higher risk tumor than they actually did. Therefore, the ISUP classification was introduced. In this classification, 3+3 tumors correspond to ISUP 1, that indicates the cathegories who have the lowest risk. In more than 90% of cases of ISUP 1 adenocarcinomas, the tumors are not able to give metastases. Since there is a large prognostic difference between ISUP 1 and ISUP 2 and 3, there are some medical doctors who are even proposing to define ISUP 1 tumors as benign. The reason why the ISUP classification has been introduced, therefore, is that it gives many information about the prognosis of prostatic adenocarcinomas. As shown in the graph on the left, ISUP 1 group has the lowest incidence of relapse following radical prostatectomy in the next ten years from surgery. Relapsing instead is much more common (almost 90%) in ISUP 5, even after radical prostatectomy, which means the tumor has somehow metastasised. 4 Take home message: Gleason score is able to predict the probability of relapse after surgery and has a prognostic value. Some exampleas of different Gleason scores: Gleason score 3+3: 3+3 score is based on isolated acinar structures. These structures can be identified well if compared to the physiological appearance of the gland; also, basal cells cannot be identified. Gleason score 4+3: Gleason score 4 is based on the fusion of acinar structures and complex structures. Inside these complex structures a “glomerular proliferation” can be observed. These structures are called pattern 4, and it’s prevalent. Gleason score 4+4: The image on the left depicts what is called a “cribriform structure”, which looks like a sieve and is characteristic of pattern 4. It’s given by the extensive fusions of acinar glands. The lumen cannot be seen anymore. Gleason score 5+5: glands cannot be identified, the lumen cannot be identified and there is fusion among the acini. However, pattern five is also characterized by cluster of 3,4,5 cells, comedonecrosis, small solid patterns, single cells and solid nets. Sometimes some crystalloids can also be seen. Pattern 5 indicates high probability to have metastasis or biochimical relapse of PSA even after surgery. Note from the sbobinator: the professor said that he will not be this specific at the exam but it is useful for our future practice. Therefore, Gleason score has: Predictive factors: Gleason score is able to predict information about the tumor volume, the margin status and nodal metastases, starting from the day after surgery. If the tumor was 5+5, it’s almost certain that it will relapse in two years or even less. Based on Gleason scores, surgeons can therefore decide how to operate: they can choose to resect the prostate alone or with its lymphnodes, decide for or against nerve sparing. In particular, nerve sparing is important, because they control erection and the internal urethral 5  sphincter, therefore resecting them greatly worsens the quality of life of the patient. However, the decision of sparing the nerves can only be taken when the tumor is small, in situ, Gleason score is low and extraprostatic infiltration is not suspected. Extraprostatic infiltration corresponds to the staging of the gland: T2: corresponds to carcinoma in situ T3: corresponds to adenocarcinoma found outside the gland (which cannot be established only with biopsy). If a tumor is at stage 3, therefore it extends outside the gland, it may likely infiltrate the nerves, and nerves cannot be therefore spared. Prognostic factors: meaning the probability to progress after surgery, or during radiotherapy, or during active surveillance. The importance of this is that it allows to avoid surgery when surgery is not needed. Immunocytochemical markers for diagnosis of adenocarcinoma of the prostate: Used to facilitate diagnosis, immunocytochemistry is a staining method based on the idea that adenocarcinomas of the prostate lack the basal cell layers (so they have only one layer). Basal cell markers: when cells lack these markers it means it’s an adenocarcinoma, on the contrary, if they express these markers, it’s not an adenocarcinoma: 1) P63 2) Cytokeratin 34betaE12 Secretory cell markers: if these markers are identified in cells of distant sites, it most likely is a metastasis of a prostatic tumor because the following markers are very specific for prostatic cells, both normal and metastatic. 1) P504 (AMACR) 2) PSA 3) NKX3.1: used more commonly, it’s a nuclear marker. For example, in the image on the left, the cells do express p63, and therefore this is not an adenocarcinoma. Instead, the gland on the right may appear neoplastic because of the projections inside the lumen of the gland, however it expresses cytokeratin 34betaE12 and therefore it’s just an hypertrophic gland. Projections are characteristic of hypertrophy. Resection margin evaluation: this concept is important to evaluate biochemical relapse after surgery. This evaluation can be carried out after prostatectomy but also during surgery. Intraoperatory evaluation: it’s important to decide when to perform or not nerve sparing. When the margin is positive nerves cannot be spared. During surgery a frozen section with inked margin is produced, so as to be able to obtain an hematoxylin-eosilin staining in few minutes (while the normal staining take 24 hours). Multiple slides are obtained. This technique is not really important to understand 6  the precise localization of the tumor, it’s much more important to evaluate margin involvement. In the second image to the right, a perineural invasion of the tumor can be oberved. Note that prostate adenocarcinomas have high affinity for nerve infiltration. Based on the type of tumor, margin positivity parameters change. For example, in pancreatic ductal adenocarcinoma, a distance of less than 1cm from the margin is considered positive. Another example, in breast cancer there is margin positivity if the tumor is located less than 5 mm from the margin. For prostate cancer it’s different, because to be considered positive, the tumor must directly be on the inked margins. Therefore, in the second image on the right in the previous page, even though the tumor is very close to the margin, margin involvement is not considered positive. Note that margin positivity is a strong predictor of poor prognosis. In fact, a pT2 with margin positivity has a worse prognosis than a pT3 tumor without margin positivity. Of course, a pT3 has by far the worst prognosis. (In the image on the left R1 indicates margin positivity). Also, the Gleason score of the part of the tumor that has infiltrated the margin is correlated to prognosis: an infiltration of the margin by a 3+3 tumor has a better prognosis than an infiltration by a 4+4 tumor and so on. Cancer progression: tumor infiltration can be: Locally avanced adenocarcinoma: a prostatic adenocarcinoma can infiltrate: 1) The bladder neck 2) The seminal vescicles 3) The Denonvillier fascia Metastatic adenocarcinoma: can occur via two routes: 1) Nodal metastasis: involves inguinal or otturatory lymphnodes. 2) Hematogenous metastasis: a primary prostatic tumor can infiltrate the adjacent pubic bones, the lungs and the liver (three most common sites) PT4: extension of the tumor to another organ. The common sites of extension vary for each T4 tumor; for example, common extension of a T4 lung tumor is the esophagus or the bones of the thorax. Another example is for T4 colorectal cancer: the most common extension sites are the peritoneum and the prostate. 7 ASAP= Atypical small acinar proliferation ASAP is not a diagnosis but only an histological description. It’s an indication of something abnormal that is not quite a neoplasia (message for the urologist). This description should indicate to the urologists that the best course of action is to perform a new biopsy in about 6 months. Even though ASAP is not a diagnosis, the probability to diagnose adenocarcinoma upon new biopsies is 10 to 45%. Therefore, it cannot be said that ASAP is a preneoplastic lesion, but it could be a risk factor for the actual developement of a prostatic tumor. Less frequent prostatic cancer histotypes: every other type of tumor of the prostate that is not acinar adenocarcinoma is by definition an high risk, high grade tumor. 1) Ductal adenocarcinoma: occurs in less than 5% of cases, but it’s very aggressive and it’s 4+4 or 4+5 by definition, therefore it’s high risk. 2) Mucinous adenocarcinoma: it’s the same type of tumur as colloid carcinoma that affects the colon. 3) Urothelial carcinoma: it is the same tumor as bladder cancer 4) Neuroendocrine carcinoma: very rare tumor, it is the same tumor as one variant of lung cancer. 5) Basal cell carcinoma: these are particular tumor because they develop from the very same cells that cannot be found in the great majority of prostate tumors, which is represented by acinar adenocarcinoma. 6) Carcinomas with squamous differentiation: like tumors of the skin. 7) Metastases from other organs: from the colon, liver, the lungs and kidneys. But this is very rare. 8 Ductal adenocarcinoma: typically present a complex pattern. Mucinous adenocarcinoma: characterized by mucous secretions that can be observed in the image on the left. Small Neuroendocrine tumor: so-called small cell carcinoma 9