Introduction

Early detection of cancer is an important issue in the field of oncology. The prostate gland is no exception to this rule. The routine screening of the vulnerable elderly male population with the three pronged approach: digital rectal examination, transrectal ultrasound and estimation of PSA in serum has led to marked increase in the frequency of prostatic biopsies. This surveillance has given rise to detection of many patients with small sized cancers, considered ideal for radical prostatectomy. The pathologist is called upon to report on prostatic biopsy and it can pose many pitfalls in the accurate interpretation. Prostatitis, Benign prostatic hyperplasia and carcinoma cover almost the entire spectrum of prostatic diseases. Virtually all problems in the interpretation of prostatic biopsies pertain to an accurate diagnosis and grading of carcinoma of prostate.

Non-Neoplastic Lesions

In chronic prostatitis, the inflammatory infiltrate may lead to distortion and atypia of the acini and this glandular abnormality may be misinterpreted as adenocarcinoma. Granulomatous Prostatitis is basically a histiocytic response to destruction of the glandular epithelium and consequent release of secretary products in the stroma. It has to be distinguished from tuberculosis. Squamous metaplasia is often seen near an infarct and this change has no precancerous role.

Adenocarcinoma

It is mainly the architectural features that help accurate diagnosis of adenocarcinomas, particularly when it is well differentiated (Fig 1). In these cases, the presence of prominent nucleoli is a very dependable diagnostic criterion. One of the most common grading used is based on degree of nuclear anaplasia (nuclear grade 1,2 and 3 ) and glandular differentiation ( well, moderately and poorly differentiated ). The two parameters, individually or combined, have been found to provide a good prognostic index [₁] and this system has been approved by the WHO.

Figure 1

Figure 1: Fairly uniform glands devoid of nuclear anaplasia showing loss of orientation and infiltrative pattern diagnostic of well differentiated adenocarcinoma H & E x 200

Grading: Gleason's score

There are many grading systems, but the one described by Gleason (1974) [₂] is currently the most popular the world over. It is based entirely upon the architectural pattern (Figs 2, 3 & 4) and the grading (grades 1 to 5) is irrespective of nuclear anaplasia. The Gleason's Score includes summation of predominant (primary) and second most prevalent (secondary) grades. If there is only a single pattern in all parts of cancer bearing biopsy tissue the single grade is doubled to arrive at the score. There are, thus 2-10 scores. Scores 2-4 roughly correspond to well differentiated adenocarcinoma, 5-7 to moderately differentiated adenocarcinoma and 8-10 to poorly differentiated adenocarcinoma. Many investigators are convinced that Gleason's score is the best predictive prognostic indicator of the biological behavior of this cancer. Fifteen year cancer specific mortality rates with Gleason's score in 767 men aged 55-74 years at diagnosis managed conservatively (no surgery or radiation therapy ) were found to be as under [₃] :

Figure 2

Figure 2: Adenocarcinoma Gleason Grade 3 H & E x100

Figure 3

Figure 3: Adenocarcinoma: Gleason Grade 2 (left upper) and Grade 4 (right lower) H & E x 200

Figure 4

Figure 4: Adenocarcinoma: Gleason Grade 5

Figure 5

Table 1: Correlation of mortality rate with Gleason's score (in patients treated conservatively)

Patients with small volume cancer of grade 2-4 have a low mortality ( 4%-7% ) and it is up to the clinician whether to offer conservative treatment. It is evident that there is a steep rise in mortality from grade 7 onwards. Lilleby and others [₄] analyzed the grades of 178 cases and compared the three-tier system of WHO with three tier clubbed Gleason's score and the results were as follows:

Figure 6

Table 2: Clubbed Gleason's scores and corresponding WHO grade

Gleason's grading system became more acceptable because the grades can be stratified into 9 categories as against the three categories ( grades ) used in the WHO and other grading systems. In the table above, it is clear that Grade II in WHO system contains 130 cases, which include moderate and also high-grade tumours. These authors, divided the Gleason's system into two tiers:

Gleason 2-6 + Gleason 7a ( 3+4 ) = 88 cases, favourable group

Gleason 8-10 + Gleason 7b ( 4+3 ) = 90 cases, unfavourable group

Gleason score 7a ( 3+4 ) has better prognosis that Gleason score 7b( 4+3 ). It was concluded that two tier Gleason system has more discriminating power in predicting prognosis of prostatic adenocarcinomas.

The histology report should comment upon lymphatic invasion. The latter consists of tumor cells within endothelium lined spaces and has been reported in 35% of radical prostatectomies. The presence of lymphatic invasion indicates extra prostatic extension, (62%) and lymph node metastasis in many cases, (67%). Perineural lymphatic invasion ( Fig 5 ) is a mechanism by which the cancer spreads in periprostatic soft tissues. This has been reported in 38% to 93% of cases of radical prostatectomies. [₅]. In a few problematic cases, perineural invasion may be the sole diagnostic criteria but unfortunately it is encountered in as low as 4.7% of prostatic biopsies (Table III ) [₆]. The presence of blue glandular mucin has been described as a useful parameter although some believe that it is a non-specific finding. Crystalloids, sharp needle like eosinophilic structures and collagenous micronodules are a specific but infrequent finding in prostatic adenocarcinoma. and we have not encountered any case with these morphological features ( Table III ).

Figure 7

Figure 5: Perineural lymphatic invasion: note neoplastic glands encircling the pale staining nerve twig H & E 400

Immunohistochemistry

Immunostaining for high molecular weight keratin is very useful in biopsies suspicious of adenocarcinoma. It specifically stains basal cells that are present in normal glands and not seen in carcinoma. In foci suspicious of carcinoma, demonstration of absence of basal cells ( Fig 6 ) by this stain is diagnostic of adenocarcinoma. In 56% of cases of high grade prostatic intra epithelial neoplasm (PIN) the basal layer is only disrupted but not lacking ( Fig 7 ) [₇].

Figure 8

Figure 6: Small atypical prostatic glands suspicious of adenocarcinoma not stained with high molecular weight keratin, note the dilated large benign gland showing positive staining. Immunoperoxidase staining with Ck12 x 100

Figure 9

Figure 7: Two ducts with intraepithelial high grade neoplasia (PIN) exhibit interrupted basal layer positive for high molecular weight keratin Immunoperoxidase staining with Ck12 x 200

Immunostaining for PSA and PAP is helpful to confirm the prostatic origin of a metastatic adenocarcinoma ( Fig 8 ) and to distinguish between transitional cell carcinoma and prostatic adenocarcinoma in some situations.

Figure 10

Figure 8: Metastatic adenocarcinoma in spine stained strongly positive for PSA Immunoperoxidase x200

Prostatic Intraepithelial Neoplasia

Prostatic intraepithelial neoplasia (PIN) is a concept borrowed from the well established and universally accepted term cervical intraepithelial neoplasia. PIN is considered to be the most likely precursor of invasive carcinoma. It is characterized by cellular proliferation within preexisting ducts and glands with cytologic atypical changes bordering on carcinoma (Fig 9) [₄]. The precancerous changes were described as mild, moderate and severe dysplasia but currently the moderate and severe grades are combined and referred to as high grade PIN. Mild dysplasia ( low grade PIN ) is considered clinically insignificant because progression to higher grade has not been reported.

Figure 11

Figure 9: Intraductal proliferation of carcinomatous cells (PIN) H & E x100

PIN coexists with cancer in more than 85% of cases. High grade PIN in biopsies generally predicts the presence of cancer in subsequent biopsies. If a biopsy reveals only pure PIN then the patient has to be subjected to repeat biopsies and kept under surveillance. PIN is least likely to be encountered in transurethral resections because 86% of PIN occurs in the peripheral zone. However, the mean incidence of finding PIN in needle biopsies is only 5% to 6%.

The precancerous role of PIN is not universally accepted Harvei et al [₈] believe that there is still lack of proof that PIN is a true premalignant lesion. We reviewed 64 cases of prostatic adenocarcinoma on needle biopsy and found PIN in only 7 cases. No instance of PIN was encountered in noncancerous prostatic biopsies.

Suspicious But Not Diagnostic Of Carcinoma

In some biopsies, there is a localized proliferation of small acini that is suspicious for carcinoma but falls just below the diagnostic threshold. The reported incidence is 1.5% to 9% of prostatic biopsies in unselected series' [₉]. The problem is caused by the small size of the focus and may represent a minimal volume prostatic adenocarcinoma, defined as involving less than 5% of the biopsy tissue. Serial sections need to be studied, as some investigators have shown that the diagnostic yield of additional sections revealed definitive carcinoma in 10% to 36% of cases [₁₀].

Iczkowski and others [₉] proposed the term atypical small acinar proliferation. All these patients diagnosed as having small acinar proliferation should be subjected to a repeat biopsy. The likelihood of prostatic cancer on subsequent biopsy in cases with initial suspicious lesion varied from 21%-49% [₉, ₁₁,₁₂,₁₃,₁₄] in different series'. Allen et al reported that cancer was identified on re-biopsy at the same sextant site as the initial atypical biopsy in 48%.

Supportive Diagnostic Criteria in Difficult Cases of Adenocarcinoma

We reviewed 127 prostatic biopsies carried out at the Jaslok Hospital in the last two years and looked for the supportive criteria reported by Epstein.[₆]. In 63 cases there was no malignancy in the biopsy. There were 64 cases of adenocarcinoma and the ages ranged from 40 to 85 years,

Epstein (1995) reviewed 434 prostatic biopsies referred to him for diagnostic problems [₆]. He described many parameters other than architecture and presence of nucleoli, which are helpful for a definitive diagnosis.

Figure 12

Table 3: Supportive criteria for diagnosis of adenocarcinoma

Lesions Mimicking Adenocarcinoma

Adenosis (atypical adenomatous hyperplasia)

Atrophy & Postatrophic Hyperplasia

Basal Cell Hyperplasia

Basal cell hyperplasia consists of a proliferation of basal cells in two or more layers near the basement membrane (Fig 10) of the prostate acini. The cells are immunoreactive for high molecular keratin (34BetaE12 keratin) and this will distinguish the lesion from adenocarcinoma. Other conditions with basal cell proliferation include basal cell adenoma and adenoid basal cell carcinoma [₁₅], both rather rare.

Figure 13

Figure 10: Two prostatic glands show marked basal cell proliferation and these cells form several layers H & E x200

Rare Types of Malignant Tumors of Prostate

Some rare types of carcinomas detected in the prostate include ductal adenocarcinoma (“endometrioid” carcinoma) mucinous adenocarcinoma and small cell carcinoma. All these are aggressive tumours in comparison to the conventional adenocarcinoma. A few may respond to hormonal manipulation. Transitional cell carcinomas are also seen in prostatic biopsies but often represent an extension of primary in urinary bladder.

Sarcomas

Sarcoma of prostate is very rare. Sextan et al [₁₆] reported 21 cases of adult prostate sarcoma and found leiomyosarcoma in 12 and rhabdomyosarcoma in 4. Sarcomas in children are mostly rhabdomyosarcomas. In our series ( Table VI ) of 7 cases there was one osteosarcoma, an almost anecdotal occurrence.

Figure 14

Table 4

In our series, WHO grading system was employed in cases of prostatic carcinomas as of 1996. Table V gives the incidence of various grades according to gleason's system in both transrectal biopsies and TUR specimens.

Figure 15

Table 5: Carcinoma of Prostate in biopsy & TUR

The Role Of Prostatic Needle Biopsy In Diagnosis, Staging And Prognosis

Negative Biopsy In Suspected Case of Prostatic Carcinoma

Indications for Repeat Biopsies

Accurate Evaluation of Grade & Prognosis on Prostate Biopsy

Volume of Cancer in the Needle Biopsy Specimen

Clinically Significant Cancer

Adjuncts to Biopsy Interpretation

DNA Ploidy

Molecular Markers

Acknowledgements