Pathology

UROLOGICAL SURVEY

Pathology

False positive labeling of prostate cancer with high molecular weight cytokeratin: p63 a more specific immunomarker for basal cells

Ali TZ, Epstein JI

Departments of Pathology, Urology Section Oncology, The Johns Hopkins Hospital, and Department of Pathology, University of Maryland Medical Center, Baltimore, MD, USA

Am J Surg Pathol. 2008; [Epub ahead of print]

Occasional nonspecific staining of prostate cancer cells with high molecular weight cytokeratin (HMWCK) can lead to false-negative diagnoses. We compared p63 and HMWCK immunostaining to check their specificity for basal cell identification. Out of 6887 prostate cancer cases sent in consultation to one of the authors over 1.5 years, we identified 22 (0.3%) cases with HMWCK labeling of cancer cells, including 20 needle biopsies and 2 transurethral resections of prostate (TURP). Cases were sent in consultation because of the confusing immunostaining pattern, where prostate cancer cells labeled with HMWCK at the outside institutions. In 6 cases, p63 immunostains were also received from the outside institution, whereas in the remaining 16 cases p63 immunohistochemistry was performed at our institution. In 14 cases, we used either an extra destained hematoxylin and eosin slide or a negative control slide for immunohistochemistry with antibodies to p63, and in the 2 remaining cases submitted unstained slides were used. The Gleason scores were 3+3=6 in 20 cases and 4+4=8 in 2 cases. The size of the tumor on needle biopsy ranged from 0.5 to 6.0 mm (mean 1 mm) and on the 2 TURP cases consisted of 44 and 68 cancer glands, respectively. The number of tumor cells positive for HMWCK in each of the needle biopsy cases ranged from 3 to 48 (mean 13 cells), whereas on the 2 TURP cases 26 and 10 cells were labeled with HMWCK. Corresponding stains for p63 on the same cases were negative in 18 cases. In 3 of 4 cases, p63 labeled 1, 1, and 2 tumor cells, respectively. The fourth case had 5 positive cells on p63 staining with 4 positive for HMWCK. To assess whether overstaining was a factor, we evaluated the intensity of HMWCK staining in the basal cells of the benign glands, which was moderate in 6 and strong in 16 cases. The cytoplasm of benign secretory cells showed focal weak (n = 3), diffuse weak (n = 1), and focal moderate (n = 2) staining for HMWCK. HMWCK labeling of prostate cancer cells is uncommon and does not seem to be solely attributable to overstaining. p63 is a more specific marker for basal cells than HMWCK, with less labeling of tumor cells. Recognition of this phenomenon and performing stains for p63 when it occurs can help prevent underdiagnosing prostatic carcinoma.

Editorial Comment

On a previous published study from the same Institution, it was shown that prostate adenocarcinoma cells may show aberrant expression for p63 immunostaining (1). In this study they describe another rare occurrence of aberrant expression: positivity for high-molecular weight cytokeratin (HMWCK). Both p63 and HMWCK are markers for basal cells which are absent in neoplastic acini.

Both are important reports of a pitfall for the pathologist while diagnosing prostate cancer. It is important for the urologist to know that immunohistochemistry is used only in some selected cases with difficult differential diagnosis and not routinely in all cases showing adenocarcinoma. More importantly, the urologist must know that even using immunohistochemistry the diagnosis may not be definitive, that is, it may be yet "suspicious but not diagnostic of adenocarcinoma”.

Why this happens? There are several benign conditions mimicking adenocarcinoma that show absence of basal cells in some of the acini: partial atrophy (2), adenosis, small branches of normal acini, and atypical PIN (PINATYP) (3). In small lesions using immunohistochemistry, these conditions may show absent basal cells in all of the acini, and in absence of other criteria for the diagnosis of cancer the pathology report is still "suspicious but not diagnostic of adenocarcinoma”.

Dr. Athanase Billis

Full-Professor of Pathology

State University of Campinas, Unicamp

Campinas, São Paulo, Brazil

E-mail: [e-mail]

Grading of invasive cribriform carcinoma on prostate needle biopsy: an interobserver study among experts in genitourinary pathology

Latour M, Amin MB, Billis A, Egevad L, Grignon DJ, Humphrey PA, Reuter VE, Sakr WA, Srigley JR, Wheeler TM, Yang XJ, Epstein JI

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA

Am J Surg Pathol. 2008; 32: 1532-9

The distinction between cribriform Gleason pattern 3 and 4 prostate cancer is controversial. Out of 3590 prostate cancers sent to one of the authors over 7 months, 30 needle biopsy cases were selected that possibly represented cribriform Gleason pattern 3 cancer. Thirty-six digital images were taken and sent to 10 experts in prostate pathology. Consensus was defined when at least 7/10 experts agreed on the grade. Sixty-seven percent (n = 24) of images reached consensus (23 pattern 4; 1 pattern 3). Of the 12 nonconsensus images, 7 were favor pattern 4 (6/10 experts agreed), 1 was favor pattern 3 (6/10 experts agreed), and 4 were equivocal (< 6 experts agreed). The most common criteria used to call pattern 4 in the 23 consensus pattern 4 images were in frequency: irregular contour, irregular distribution of lumens, slit-like lumens, large glands, number of glands, and small lumens. In the only consensus pattern 3 image, criteria used were regular contour, small glands, regular distribution of lumens, and uniform round lumens. Discrepancy between experts was qualified as primarily objective (different criteria present) in 38%, subjective (different interpretation of the same criteria) in 12%, and mixed (both objective and subjective) in 50%. The most frequent situation with different interpretations of the same criteria were regular versus irregular contour and small versus large glands, with the former more common. Even in this highly selected set of images thought to be the best candidates for cribriform pattern 3 from a busy consult service, most experts interpreted the cribriform patterns as pattern 4. Moreover, most of the cribriform foci investigated (73%) were associated with more definitive pattern 4 elsewhere on the needle biopsy specimen. In conclusion, most of the small cribriform cancer foci seen on needle biopsy should be interpreted as Gleason pattern 4 and not pattern 3.

Editorial Comment

The cribriform pattern (glands in glands) is a very peculiar arrangement frequently seen in adenocarcinoma of the prostate. In metastases of unknown origin, this pattern seen in older men is almost always adenocarcinoma from the prostate. Obviously this pattern is not exclusively seen in prostate cancer. It may also be seen in carcinoma of the breast, gastrointestinal tract and other organs.

In the standard Gleason grading, cribriform pattern could correspond to patterns 2, 3, or 4. In the revised Gleason grading published in 2005 (1), cribriform pattern should never correspond to pattern 2, and very rarely to pattern 3. Most of the times it corresponds to grade 4. Cribriform pattern 3 is only diagnosed for well circumscribed glands of the same size as normal glands.

Reference

Dr. Athanase Billis

Full-Professor of Pathology

State University of Campinas, Unicamp

Campinas, São Paulo, Brazil

E-mail: [e-mail]

• 1. Osunkoya AO, Hansel DE, Sun X, Netto GJ, Epstein JI: Aberrant diffuse expression of p63 in adenocarcinoma of the prostate on needle biopsy and radical prostatectomy: report of 21 cases. Am J Surg Pathol. 2008; 32: 461-7.
• 2. Wang W, Sun X, Epstein JI: Partial atrophy on prostate needle biopsy cores: a morphologic and immunohistochemical study. Am J Surg Pathol. 2008; 32: 851-7.
• 3. Kronz JD, Shaikh AA, Epstein JI: High-grade prostatic intraepithelial neoplasia with adjacent small atypical glands on prostate biopsy. Hum Pathol. 2001; 32: 389-95.
• 1. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP Grading Committee: The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005; 29: 1228-42.

Publication Dates

• Publication in this collection
  16 Dec 2008
• Date of issue
  Oct 2008