Specimen

— fine needle aspirate/needle core biopsy (18 gauge)/transurethral resection (TUR) chippings/radical prostatectomy (including seminal vesicles) and regional lymphadenectomy.

— symptomatic prostatic cancer is often indicative of widespread disease with lumbar pain as a result of bone metastases. It may also present with prostatism but is frequently detected because of an elevated serum PSA with digital rectal examination (DRE) either as part of a screening programme or a family practitioner's well man check-up. Further investigation comprises transrectal ultrasound (TRUS) to identify classical tumour-related hypoechoic areas. Because 70% of prostatic cancer is present posteriorly and peripherally this is coupled to per rectum clinical or TRUS-directed needle core biopsies (clinical: right/left/transitional zone; TRUS: sextant/3 samples each side aimed at apex/mid/base regions). Recent evidence shows that a percentage of cancers are isoechoic and an extended 10-core biopsy regime has been advised. The resultant fine biopsy cores need careful handling, wrapping and painting with alcian blue prior to processing to allow their visualization at the block cutting stage. Otherwise initial block trimming may result in loss of diagnostic tissue. Blocks are cut through at least three histological levels and the intervening ribbons kept pending any subsequent need for immunohistochemistry. Microscopic assessment is at low power looking for abnormalities of glandular architecture and medium to high power to confirm cytological features of malignancy. The biopsy report should indicate which biopsy site is positive, the Gleason tumour grade, the number of positive cores and percentage of involved tissue. It may be possible to comment on other staging information, e.g. spread into extracapsular fat or neurovascu-lar bundles, or involvement of seminal vesicles. Another indication for prostatic biopsy is a rising serum PSA after radiotherapy or brachytherapy for a previously proven cancer. Reasons for a repeat biopsy are an insufficient index biopsy, features suspicious but not diagnostic of malignancy, high-grade PIN and a rising serum PSA after a negative biopsy. Treatment of prostatic cancer is age, fitness, grade and stage-dependent ranging from watchful waiting to hormonal therapy (androgen deprivation) for focal and locally advanced or metastatic disease, respectively. Metastatic disease is assessed by radioisotope bone scan while CT scan and MRI scan have limited sensitivity for local spread. Radical prostatectomy is aimed at younger patients (50-65 years) with low to modest elevations in serum PSA who are more likely to have gland-confined disease and negative surgical margins. It is an operation with significant morbidity and side-effects (e.g. incontinence, impotence), some of which may be avoided by a selective nerve-sparing procedure, although this can have implications for the completeness and tumour clearance of margins. An equivalent alternative with fewer complications is radical radiotherapy and there is also increasing use of brachytherapy (radioactive seed implants) or cryotherapy of the tumour and its bed. Preoperative combination therapy can downsize tumour while post-operative radiotherapy and/or chemotherapy are based on the Gleason component and sum scores, margin status and extracapsular disease. Prostatic chippings piece-meal resect the periurethral and central zones and TURP is performed in two main situations: a. in patients with benign hypertrophy of the medial aspect of the gland who have persistent troublesome pro-statism (urinary frequency, hesitancy, dribbling) that is refractory to medical therapy or who develop acute urinary retention, or b. TURP channel re-do in a patient with known cancer and significant prostatic symptoms. In the former incidental cancer may be detected histologi-cally (8% of cases) and the significance of this is then interpreted in light of the patient's serum PSA and clinical staging.

Tumour

Site

— inner (transitional)/outer (central and peripheral) zones. The transitional zone surrounds the proximal urethra and the central zone is posterior to it. The peripheral zone occupies 70% of the gland in a horseshoe shape around its posterior and lateral aspects.

— medial/lateral (right or left) lobes. These are not defined anatomical structures but relate to clinically palpable masses on per rectum examination. For the purposes of TNM staging the gland is notion-ally divided into right and left lobes about a mid-point sagittal plane

— posterior/subcapsular.

— the majority of carcinomas are posterior and peripheral with multi-centricity present in up to 75% of cases.

Size

— length x width x depth (cm) or maximum dimension (cm).

— tumour volume (cm3). Derived by outlining and calculating the area of tumour in each slide and then multiplying by the mean block thickness (the anteroposterior diameter divided by the number of coronal slices). The volume is the sum total for all the blocks/slides. Alternatively, a quicker method is to outline the tumour in each slide, lay them out on the bench and estimate the total percentage area involved, e.g. 60%. Knowing the gland volume (AP x width x depth) the tumour volume is presumed to be 60% of it, assuming even tumour distribution throughout each block. Clinicians vary in the use of these data but pragmatically they gives an indication of the risk of extracapsular disease. It is also useful for correlation with serum PSA and TRUS assessment along with tumour site location. However, its importance is far outweighed by that of consistent Gleason scoring and assessment of the capsule and margin status. Given the heterogeneity of tumour distribution within the prostate, volume estimates are more accurate based on whole gland serial slices and processing. This can mean 40-50 slides for a small gland using routine blocks. Two alternatives are: a. whole mount sections that reduce the block numbers and allow easier assessment of lobar tumour distribution, or b. a sampling strategy to include the base and apical margins, seminal vesicles, all posterior sections and a mid-slice of the anterior prostate on either side. In needle biopsy and TURP specimens the number of cores and percentage of chippings involved are routinely given in the surgical histopathology report.

Appearance

— pale/yellow/granular.

Similar changes are seen in tuberculosis, infarction, granulomatous prostatitis and acute and chronic prostatitis, i.e. tumour is difficult to define macroscopically and histological assessment is necessary.

Edge

— circumscribed/irregular.

2. HISTOLOGICAL TYPE Peripheral acinar/duct origin

Adenocarcinoma with acinar, diffuse single cell infiltration, papillary, cribriform, comedo patterns

• acini are usually small to medium in size and can be rounded or angular in contour. Diagnosis is made at low-power magnification on the basis of a gland-rich haphazard infiltrative pattern in comparison with and between ducts of adjacent benign prostatic tissue. Medium to high power can then confirm the lack of an epithelial bilayer and nuclear characteristics of malignancy (enlargement/angularity/membrane folds/nucleolar prominence). Luminal crystalloids may also be present. Cribriform and comedo patterns resemble intraductal carcinoma and can be difficult to distinguish from high-grade PIN (Prosta-

tic Intraepithelial Neoplasia), but again are architecturally too ductal-rich compared with adjacent tissues. Diagnostic pitfalls are large gland, atrophic and pseudohyperplastic variants of carcinoma which can resemble post atrophic or benign hyperplastic prostate. Occasionally clear cell or foamy gland adenocarcinoma is encountered to be distinguished from cytokeratin negative/CD68 positive aggregates of xanthomatous histiocytes. Notably these well differentiated carcinoma variants are negative for the basal layer cytokeratin marker 34|3E12.

Mucinous adenocarcinoma

— distinguish from secondary colorectal or bladder cancer by a relevant past history and also usually CK7/CK20 negative. Variable PSA/PSAP expression.

— >25% of the tumour area is intra-/extracellular mucin.

— fewer bone metastases and less hormone/radioresponsive than usual prostatic carcinoma.

Signet ring cell adenocarcinoma

— rare; distinguish from secondary gastric or colorectal cancer by a relevant past history and also usually CK7/CK20 negative. Variable PSA/PSAP expression.

— >25% of the tumour area is signet ring cells, usually coexisting with other poorly differentiated carcinoma and of poor prognosis.

Basal cell carcinoma

— a morphological continuum from typical through florid basal cell hyperplasia/adenoma to carcinoma with infiltrative edges, stromal desmoplasia, comedonecrosis and adenoid cystic-like differentiation. 34PE12 positive and a tumour of variable malignant potential.

Undifferentiated, small cell type carcinoma

— CAM5.2/synaptophysin/CD56 positive. Immunonegative cases are classified as poorly/undifferentiated prostatic carcinoma.

— lung small cell carcinoma analogue.

— primary or secondary from lung, pure or mixed (25%) with usual prostatic carcinoma ± an associated bladder component.

— aggressive: sometimes inappropriate ACTH/ADH secretion.

— carcinoid tumour is rare. Up to 33% of usual prostatic carcinomas can show neuroendocrine differentiation on immunohistochemistry and this is usually of no prognostic significance.

Adenosquamous/squamous carcinoma

— rare and poor prognosis. Exclude squamous metaplasia due to infarction or hormone therapy, or spread from bladder or anal cancer.

— up to 50% may arise in prostate cancer patients after endocrine or radiotherapy.

Lymphoepithelial carcinoma

— analogous to nasopharyngeal carcinoma.

Sarcomatoid/spindle cell carcinoma

— syn. carcinosarcoma or metaplastic carcinoma.

— cytokeratin positive spindle cells with variable malignant stromal mesenchymal differentiation which is usually homologous ± heterologous elements (bone, cartilage, striated muscle).

— older men, variable prognosis.

Central (large) duct origin

Periurethral duct adenocarcinoma

— old age and polypoid/villous or infiltrative on cystoscopy. Has a more advanced stage at presentation and is aggressive. May be associated with a diverticulum.

— variable papillary, cribriform and endometrioid patterns (uterine carcinoma analogue). Prostate specific antigen/prostatic acid phosphatase (PSA/PSAP) positive, ±oestrogen sensitive.

— associated Paget's disease of the prostatic urethra.

— exclude secondary renal clear cell carcinoma if mesonephroid or hob-nail clear cell in type.

Transitional cell carcinoma

— arise from the transitional cell lining of the prostatic urethra or proximal periurethral ducts.

— usually high grade with extension into ducts, central comedonecrosis ± adjacent stromal invasion, the presence of which is the strongest prognostic indicator.

— exclude spread from a bladder transitional cell carcinoma.

Mixed acinar/large duct types and adenocarcinoma/transitional cell carcinoma

Metastatic carcinoma

— direct spread: bladder (in 40% of radical cystoprostatectomies for bladder cancer), colorectum, anus, retroperitoneal sarcoma.

— distant spread: kidney, lung (squamous carcinoma), malignant melanoma.

3. DIFFERENTIATION/GRADE

Well/moderate/poor/undifferentiated, or Grade 1/2/3/4.

— well/G1 = Gleason sum score 2-4; moderate/G2 = Gleason 5-6; poor/G3 = Gleason 7-10.

— 50% of cases show heterogeneity of tumour grade.

— signet ring cell carcinoma is poorly differentiated (grade 3) and small cell carcinoma undifferentiated (grade 4). Specific carcinoma variants can be allocated a Gleason score, e.g. mucinous adenocarcinoma (pattern 4), small cell carcinoma and signet ring cell (pattern 5) but scoring is more applicable to usual type prostatic adenocarcinoma.

Pattern 1: Closely packed, single, separate, round uniform glands; well defined tumour margin

Pattern 2: Single, separate, round, less uniform glands separated by stroma up to one gland diameter; tumour margin less well defined

Pattern 3: Single, separate, irregular glands of variable size, enlarged masses with cribriform or papillary pattern; poorly defined tumour margin

Pattern 4: Fused glands in mass with infiltrating cords, small glands with papillary cribriform or solid patterns; cells small, dark or hypernephroic (clear cells)

Pattern 5: Few or no glands in background of masses with comedo pattern, cords or sheets of tumour cells infiltrating stroma

Figure 31.1. Gleason score in prostatic carcinoma. (Gleason DF. The Veterans Administration Cooperative Urologic Research Group: Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M (ed) Urologic pathology: the prostate. Philadelphia: Lea and Febiger, 1977.).

Gleason score for usual prostatic adenocarcinoma

The Gleason system proposes that any given prostate carcinoma may show one or several of five histological glandular architectural patterns ranging from the lowest grade (grade 1) to the highest grade (grade 5). Taking the two predominant patterns one can arrive at a score (e.g. 2 +3 = 5; 3 + 4 = 7) which has prognostic significance. The following rules apply:

(a) choose the two predominant patterns where more than two are present

(b) when there is only one pattern, double it, e.g. 3 + 3 = 6

(c) in limited samples (e.g. needle biopsy, TUR chippings) where there are more than two patterns and the worst grade is neither the predominant nor the second most predominant pattern, choose the main pattern and the highest grade. For example, if grade 3 is 60%, grade 1 is 30% and grade 4 is 10%, the score is 3 + 4 = 7. Note that due to sampling error and crush artefact, needle biopsy samples can underestimate the Gleason score compared with the subsequent resection specimen and scoring is subject to observer variability. A useful tip when assessing Gleason score is: f for fusion and 4, i.e. packed glands

Pattern 1: Closely packed, single, separate, round uniform glands; well defined tumour margin

Pattern 2: Single, separate, round, less uniform glands separated by stroma up to one gland diameter; tumour margin less well defined

Figure 31.1. Gleason score in prostatic carcinoma. (Gleason DF. The Veterans Administration Cooperative Urologic Research Group: Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M (ed) Urologic pathology: the prostate. Philadelphia: Lea and Febiger, 1977.).

with elimination of intervening stroma. Cribriform (pattern 4) and comedo (pattern 5) areas may also be present. Where there are multiple needle biopsies or foci in a prostatectomy with different Gleason scores the score of the least differentiated areas should be recorded. Urological oncologists also like to know the component parts of the sum score (i.e. 3 + 4 = 7) as management may be based on the percentage worst element.

Note that a needle biopsy positive for prostatic adenocarcinoma is usually of at least Gleason pattern 3, i.e. small, angular individual glands infiltrating stroma. Gleason pattern 1 or 2 cancers comprise larger, uniform glands in circumscribed nodules more easily appreciated in centrally located TURP specimens. Useful guides to Gleason scoring of prostatic adenocarcinoma are found at http://pathology2.jhu.edu/gleason and from the 2005 ISUP Consensus Conference (Epstein et al. Am J Surg Pathol 2005; 29:1228-1242).

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