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The Process of Diagnosing Prostate Cancer On Needle Biopsy: Making The Diagnosis - Bahram Robert Oliai, M.D.



In this newsletter we will tackle one of the most interesting and sometimes challenging aspects of genitourinary pathology, how we make the diagnosis of prostate cancer on a small needle biopsy.

Once the core tissue has been processed and slides stained it is time for the pathologist to examine the case and render a diagnosis. The diagnosis of prostate cancer or any other pathologic diagnosis for that matter must always begin with a well trained pathologist and a good Hematoxylin and Eosin (H&E) stained slide. Initial scanning of prostate biopsies should take place at medium magnification (4X-10X objective); this allows one to appreciate any differences in glandular appearance/architecture. A key tactic which I employ in evaluating a given case is to familiarize myself with the patient's "normal" background non-neoplastic glands and acini. Once I have done this I keep a sharp eye out for anything that deviates from this pattern. It is almost as if I am an alert guard dog who after learning what belongs in my home and yard, is ready to vigorously accost any strangers wandering into my family's domicile. On low power examination carcinomatous acini stand out as they are often smaller than benign acini and have an infiltrative appearance, essentially snaking between benign glands. Another low power architectural pattern described by urologic pathologist Dr. George Netto of The Johns Hopkins Hospital is the "bubble pattern" in which atypical acini line up in a row cutting through the stroma like bubbles coming from a fish deep in the sea (FIG 1). On high power examination features of carcinoma include prominent nucleoli, enlarged hyperchromatic (fancy pathology word for darker) nuclei, mitotic figures, cytoplasmic amphophilia (fancy pathology word for purplish hue), razor sharp glandular luminal borders (as opposed to the papillary infoldings/ruffles seen in benign glands), blue tinged mucinous secretions, so-called "pink schmutz" (or amorphous secretion), and pink intraluminal crystalloids.

In summary, evaluating a suspicious focus should be a methodical process. Dr. Jonathan Epstein, of The Johns Hopkins Hospital describes developing a mental "balance sheet," with on one side a list of features favoring carcinoma and on the other a list favoring a benign diagnosis. If at the end of the case the criteria stack up in support of cancer a definitive diagnosis can be made. In this way one can see that the diagnosis of carcinoma is based on a combination of findings and not on any one atypical feature (many of which can on occasion be seen in benign glands).

Features Definitively Diagnostic of Carcinoma

Although this was covered in my previous newsletter pertaining to small foci of prostatic adenocarcinoma, I feel that given the importance of the topic a quick review is in order.

Perineural invasion is a feature seen in 1/5 of positive needle biopsies and when present is diagnostic of cancer. However, for perineural invasion to be truly diagnostic of cancer the gland must entirely encircle and completely embrace the nerve, as benign glands can indent nerves and be seen within nerve fibers (FIG 2).

Figure 1: The “bubble pattern of prostate carcinoma on needle biopsy.
Figure 2: True perineural invasion. Note how the carcinomatous gland completely embraces the nerve (center), rather than just abutting it.

Glomerulations describes a morphologic pattern in which carcinomatous glands show a cribriform pattern attached only to one side of the gland. This formation superficially resembles a renal glomerulus, hence the name (FIG 3). Glomerulations are diagnostic of cancer and often suggest Gleason's pattern 4.

Mucinous fibroplasia refers to intraluminal mucinous secretions that organize forming balls of "collagenous micronodules (FIG 4)." This is yet another feature diagnostic of prostate cancer.

Figure 3: Glomerulations are diagnostic of carcinoma and refer to a morphologic pattern of glandular infolding reminiscent of glomeruli in the kidney.

Figure 4: Mucinous fibroplasia refers to the organization of secreted mucin into pink viscid material and is diagnostic of carcinoma, as benign
glands do not produce this type of substance.

Figure 5: Prostatic carcinoma (H&E, 5a) showing negative staining with high molecular weight cytokeratin and p63 in a basal cell distribution and showing intense cytoplasmic staining with racemase (P504S, 5b).

Figure 6: HGPIN The micropapillary structures are composed of atypical cells with enlarged nuclei, prominent nucleoli, and a loss of polarity.
Occasionally extraprostatic extension can be diagnosed on needle biopsy. According to internationally known Johns Hopkins Surgical Pathologist Pedram 
Figure 7: PINATYP. Although there are atypical glands which in and of themselves are worrisome for cancer, they are all in close vicinity to a larger HGPIN gland and tangential sec-tioning or “budding off” of the HGPIN gland cannot be ruled out. 
Occasionally extraprostatic extension can be diagnosed on needle biopsy. According to internationally known Johns Hopkins Surgical Pathologist Pedram "Pete" Argani "There's no crying in baseball and there's no fat in the prostate." Hence malignant glands detected in adipose tissue on needle biopsy are diagnostic of extraprostatic extension.

Atypical Acini/High Grade PIN

Another topic which I have previously covered in a newsletter, but which I feel is deserving of review is that of so-called "atypical acini."

Sometimes small foci are noted, which while morphologically suspicious for cancer do not seem to fulfill enough morphologic criteria for the diagnosis or are so few in number that a diagnosis cannot be reached (the mental balance sheet does not add up). In such cases special stains for basal cells (high molecular weight cytokeratin, p63) and racemase (P504S or AMACR) can be used to help support a diagnosis of cancer (by an absence of basal cells in the atypical acini and positive racemase staining, FIG 5). At ProPath we can evaluate these small foci through the use of tissue protection Immunohistochemistry, thanks to our in house world class Immunohistochemistry laboratory under the direction of expert Dr. Rodney Miller. Again, all pathologic diagnoses must start with a well trained pathologist and an H&E stained slide and I do not recommend routinely staining all core tissue with these stains in the absence of an atypical focus on H&E. There are labs that do this and this practice can occasionally lead to overdiagnosis as inflamed glands, adenosis, and atrophy can rarely be negative for basal cell markers. In addition, this practice adds needless expense to these cases.

When stains do not resolve the issue and I still feel uncomfortable making a definitive diagnosis I label these foci "atypical acini" or "atypical acini, highly suspicious for prostatic adenocarcinoma." At this point I show the case around internally and if a more defintive diagnosis cannot be made I discuss the case with the submitting urologist. If requested I am happy to send such cases out for external expert consultation, recognizing that some prominent experts may feel more comfortable diagnosing very limited foci of cancer.

High grade prostatic intraepithelial neoplasia (HGPIN) refers to the presence of cytologic features of cancer (i.e. large dark nuclei, prominent nucleoli) in at least 10% of dysplastic intraluminal cells within glands that are architecturally benign (FIG 6). I do not diagnose low grade PIN as it is a diagnosis that is neither reproducible nor clinically relevant.

Another diagnostic difficulty occurs when small atypical acini with features of cancer are noted adjacent to glands of HGPIN. While these glands may represent early cancer they may also represent tangential outpouchings off HGPIN (FIG 7) and often there is no definite way to tell, unless the atypical glands simply numerically overwhelm the HGPIN glands.

1. The diagnosis of prostate cancer always begins with a well trained pathologist and a good H&E stained slide.
2. First familiarize yourself with the patient's natural benign prostatic glands, then keep a sharp eye out for anything that looks different (be the vigilant guard dog).
3. The diagnosis of prostate cancer should be based on a constellation of findings, nearly all of which which should support the diagnosis of cancer (make sure the balance sheet adds up).
4. Features absolutely diagnostic of cancer include true perineural invasion, glomerulations, and mucinous fibroplasia.
5. Immunohistochemical stains may help support a diagnosis of prostate cancer, but ONLY should be performed on suspicious foci, and should NEVER be the sole basis of a malignant diagnosis.
6. Small suspicious foci may be below the diagnostic threshold of cancer (although this may vary slightly from pathologist to pathologist). In cases where diagnostic conservatism is warranted, the diagnosis of atypical acini can be rendered and these patients need close followup.


Special thanks to Dr. Jonathan Epstein for his permission in using images from Epstein JI, Yang XJ. Prostate biopsy interpretation, Philadelphia: Lippincott, Williams & Wilkins, 2002.