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Histology of prostate cancer

Photomicrograph of prostate carcinoma. Click to enlarge.

Prostate cancer is a heterogeneous group of malignant tumors that are classified according to the World Health Organization (2004). Ninety-five percent of these tumors are adenocarcinoma originating from the glands and ducts in the prostate. These tumors grow multifocally in the prostate and rarely produce macroscopic tumor nodules. More than 75% of the tumors appear in the peripheral zone. This produces a change in consistency, which can be felt during rectal exploration/palpation.

Most adenocarcinomas are of the acinar type, which are usually referred to as prostate carcinomas . More than 1% of prostate carcinomas are made up of other variants that often have a poor prognosis such as ductal carcinoma , mucinous carcinoma, signet ring cell carcinoma, and small cell carcinoma . Five percent of prostate cancer cases are made up of other types originating from transitional epithelial cells in the urethra or pars prostatic urethra (urothelial carcinoma), support tissue (sarcomas) or lymphoid tissue (lymphomas). Metastases also occur in the prostate, but it is more common that tumors in neighboring organs such as the bladder, rectum, or testis, infiltrate the prostate gland. 

Histological diagnosis

When an elevated PSA value in the serum is detected and prostate cancer is suspected, the diagnosis must be verified before treatment can be started. The pathologist plays a key role in the diagnosis of prostate cancer, as important differential diagnoses such as overgrowth or metastasis from other tumors, benign lesions such as adenosis, atrophy, or prostatitis must be ruled out.

Carcinoma typing, grading, and determination of tumor extension are important information to gather before the treatment and prognosis can be evaluated. The diagnosis is often made on ultrasound-guided biopsies, but sometimes also coincidental in transurethral resections (TUR-P) performed to treat urinary problems. 

The primary cancer diagnosis is always confirmed by two pathologists. The criteria used by the pathologist are architecture atypia (invasive growth, perineural infiltration , micro and cribriform glands) and cellular atypia (enlarge nuclei with prominent nulceoli ). Small foci with carcinoma are usually confirmed by immunohistochemical techniques. With invasive adenocarcinoma, there is usually a loss of basal cells present in benign glands and, in addition, the basal cell markers 34BE12 and p63  are also lost. The marker, alpha-methylacyl-CoA racemace (AMACR/p504s), is upregulated in prostate carcinoma , and can be detected with immunohistochemical techniques.

Needle biopsies

Needle biopsies are usually performed by the urologist via the rectum using ultrasound. Using this procedure, the posterior part of the prostate is reached where most prostate cancer originates. As a rule, 4 biopsies are taken from each lobe . When an MRI or clinical examination gives suspicion of a tumor in the anterior part of the prostate, but transrectal biopsies are negative, biopsies with access through the perineum should be performed. This procedure is performed under general anesthesia.

The needle biopsies are processed separately in order for the pathologist to determine the location of the cancer growth. Additionally, the pathologist must determine how many millimeters of the total length of the biopsy shows carcinoma growth. In addition to the Gleason score, the pathologist determines if there is perineural infiltration or tumor invasion into fat tissue or the seminal vesicles.

Transurethral prostate resection (TUR-P)

During a transurethral prostate resection, the tissue from the central part of the gland is resected to decrease the chance urinary problems. This is done through a scope via the urethra where tissue is removed using a laser knife. The pathologist will receive these tissue pieces fixed in formalin. After fixation, the material is weighed, and about five to eight paraffin blocks are processed from random tissue material .

The pathologist studies the sections from this tissue to determine if benign hyperplasia is the only abnormality. Incidental carcinoma is sometimes found and, if so, the percentage of tissue pieces with carcinoma involvement is determined. Grading is then done along with typing of the tumor. It may be difficult to determine the presence of carcinoma due to heat damage of the tissue .

If the pathologist suspects carcinoma, but the diagnosis cannot be confirmed, it is recommended to take needle biopsies from the peripheral zone.

Radical prostatectomy

When the investigation demonstrates a localized tumor and the tumor grading does not indicate aggresive carcinoma, the patient is a candidate for curative treatment such as a radical prostatecomy .

Examination of prostatectomy specimens is an involved procedure for the laboratory and the pathologist. The entire gland and seminal vesicles are embedded, sectioned, and examined microscopically. This often means 40-50 microscopic sections including several whole-organ sections from the central part of the gland are examined  .

The pathologist studies all sections in detail and describes tumor extension, grade and findings such as perineural carcinoma growth, and infiltration of the seminal vesicles and vessels. It is also reported whether the capsule around the gland is intact as well as if the resection borders are free of tumor.  If the margin is infiltrated by carcinoma, its location and extension should be stated. All of this information must be taken into account when planning the follow-up and deciding on additional therapy.

A positive correlation between MRI findings and macroscopic and microscopic findings is present usually only with large tumors .

Grading

For prostate carcinoma na special grading system described by Donald Gleason is used (1966). This grading system correlates very well with prognosis and has been replacing the WHO grading system. Contrary to the WHO system, Gleason grading is only based on glandular architecture, not cellular atypia. There are 5 Gleason grades, but Gleason grade 1 is hardly ever reported/used.

Example of biopsies with Gleason grade
(click to enlarge)

Grade 2

Tumor consists of well-delineated foci of small, regular nodes almost without any obvious infiltration in the stroma.

Grade 3

Tumor consists of infiltrating nodes of varying size and with varying distance between them. They usually infiltrate between normal nodes.

Grade 4

Tumor consists of complex, cribriform and confluent glands almost without any intervening stroma. There is also often only a tendency for glandular lumina.

Grade 5

Tumor consists of diffuse growing tumor cells with either large confluents sheets, single infiltrating cells, or large groups with central coagulation necrosis.

Score 7 (3+4)

Dominating pattern is grade 3.
Secondary pattern corresponds to grade 4.

 
Dr. Gleason's simplified diagram of the five histological grades of prostate carcinoma.
 

The most aggressive tumors have a Gleason score 5. A Gleason score is given for each needle biopsy as a sum of the dominating and secondary grade. The secondary grade is provided only if it makes up > 5%. A tertiary Gleason grade 4 or 5 is reported even if it makes up < 5%. If the Gleason score is 7b (4+3), the dominating Gleason grade is 4. This grade has a significantly poorer prognosis than a Gleason score of 7a. Tumors with Gleason score 4–5 are low-grade, while Gleason score 6–7a are intermediary, and Gleason score 7b-10 are high-grade. In radical prostatectomy specimens where tumor tissue usually has multifocal extensiveness , focus is provided only on the highest Gleason score and on tertiary Gleason grade 4–5, if applicable. Aggressive tumors such as ductal carcinoma, signet ring cell carcinoma, and small cell carcinoma are not graded. With very small carcinoma foci (< 0.5 mm) the Gleason score is not given, usually only a Gleason grade, if applicable. The Gleason score is also not reported after the patient has been treated with hormone or radiation therapy.

Prostatic intraepithelial neoplasia (PIN)

It is assumed that PIN is a pre-stage for prostatic carcinoma. The changes associated with PIN were first described in 1960 and the term has been used since 1986. PIN is more common in prostate glands with carcinoma than those without. Diagnostic testing for PIN has poor reproducibility between pathologists and also for the same pathologist.  Low-grade PIN (PIN 1) is therefore not reported. The pathologist specifies only the presence of isolated high-grade PIN (PIN 2–3), and in this case, it is recommended to take new biopsies to rule out malignancy. There are different variations of high-grade PIN. If there is ambiguity in an atypical gland with cribiform growth, immunohistochemical techniques can be used. For high-grade PIN, basal cell strata are preserved .

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