|
Best practice in diagnostic immunohistochemistry:
prostate carcinoma and its mimics in needle core
biopsies.
|
|
|
|
|
| Abstract: |
Context.--The unrelenting challenge encountered when
differentiating limited-volume prostate carcinoma and sometimes subtle
variants from its many morphologic mimics has increased the use of
ancillary immunohistochemistry in routine prostate needle biopsies. The
availability of prostate cancer-associated and basal cell-associated
markers has been an invaluable addition to diagnostic surgical
pathology. Objective.--To review commonly used immunohistochemical stains, including innovative combinations, for confirmation or differential diagnosis of prostate carcinoma, and to propose appropriately constructed panels using morphologic patterns in prostate needle biopsies. Data Sources.--These best practices are based on our experience with routine and consultative case sign-outs and on a review of the published English-language literature from 1987 through 2008. Conclusions.--Basal cell-associated markers p63, highmolecular-weight cytokeratin 34[beta]E12, cytokeratin 5/6 or a cocktail containing p63 and high-molecular-weight cytokeratin 34[beta]E12 or cytokeratin 5/6 and prostate carcinoma-specific marker [alpha]-methylacyl coenzyme A (coA) racemase alone or in combination are useful adjuncts in confirming prostatic carcinoma that either lacks diagnostic, qualitative or quantitative features or that has an unusual morphologic pattern (eg, atrophic, pseudohyperplastic) or is in the setting of prior treatment. The combination of [alpha]-methylacyl coA racemase positivity with negative staining for basal cell-associated markers supports a malignant diagnosis in the appropriate morphologic context. Dual chromogen basal cell associated markers (p63 [nuclear] and high-molecular-weight cytokeratin 34[beta]E12/cytokeratin 5/6 [cytoplasmic]) and [alpha]-methylacyl coA racemase in an antibody cocktail provide greater sensitivity for the basal cell layer, easing evaluation and minimizing loss of representation of the focal area interest because the staining is performed on one slide. In the posttreatment setting, pancytokeratin facilitates detection of subtle-treated cancer cells. Prostate-specific antigen and prostatic acid phosphatase markers are helpful in excluding secondary malignancies involving the prostate, such as urothelial carcinoma, and occasionally in excluding nonprostatic benign mimickers, such as nephrogenic adenoma, mesonephric gland hyperplasia, and Cowper glands. There is no role for ordering immunohistochemistry prospectively in all cases of prostatic needle biopsies. (Arch Pathol Lab Med. 2008;132:1388-1396) |
|
|
|
| Subject: |
Prostate cancer
(Diagnosis) Carcinoma (Diagnosis) Cancer (Diagnosis) Immunohistochemistry Enzymes Thiols Antigens Keratin Phosphatases Antibodies Viral antibodies |
| Authors: |
Paner, Gladell P. Luthringer, Daniel J. Amin, Mahul B. |
| Pub Date: | 09/01/2008 |
| Publication: | Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165 |
| Issue: | Date: Sept, 2008 Source Volume: 132 Source Issue: 9 |
| Product: | Product Code: 2831600 Enzymes; 2831630 Enzymes for Food Processing; 2868885 Mercaptans NAICS Code: 32519 Other Basic Organic Chemical Manufacturing; 325199 All Other Basic Organic Chemical Manufacturing SIC Code: 2869 Industrial organic chemicals, not elsewhere classified; 2836 Biological products exc. diagnostic |
| Accession Number: | 230247132 |
| Full Text: |
The widespread use of prostate-specific antigen (PSA) serum
screening, the availability of transrectal ultrasonography to target
specific lesions of the prostate, and use of the relatively
less-traumatic, 18-gauge needle core biopsy have resulted in an
increased clinical detection of prostate carcinoma, including those
carcinomas with smaller tumor volumes, and consequently, have shifted
the threshold for its morphologic diagnosis, particularly when very few
atypical acini are present. There are 2 broad indications for use of
immunohistochemistry in prostatic pa thology: (1) in confirming prostate
carcinoma and/or distinguishing it from its many benign mimics,
including instances of unusual morphologic patterns of cancer or a
history of prior treatment (1-3); and (2) in distinguishing prostate
carcinoma from nonprostatic malignancies that secondarily involve the
prostate. (4-6) In these diagnostic settings, we propose that best
immunohistochemistry practices include a pattern-based approach and
appropriately constructed panels based on the diagnostic situation. For handling needle biopsies, we recommend that intermediate level sections be prospectively obtained on charged (gelatinized) slides for potential immunohistochemistry or additional morphologic evaluation. (7) This practice has value because atypical foci, suspicious for carcinoma, are frequently small and may not be represented on sections retrospectively obtained for immunohistochemistry. (7) DIFFERENTIAL DIAGNOSTIC CONSIDERATIONS Because of its protean morphology, the differential diagnosis of prostate carcinoma in needle biopsy includes an array of possibilities, from normal structures (eg, crowded, small acinar glands or seminal vesicle epithelium) to aggressive malignancies (eg, metastatic, poorly differentiated carcinomas). (1,2,4-6) The considerations vary based on the pattern encountered in the needle biopsy and include atypical small acinar proliferation (ASAP), atypical large glandular proliferation, and infiltrative single cell patterns, among others (Table 1). This discussion is restricted to the role of immunohistochemistry in more common diagnostic scenarios encountered in routine surgical pathology, where an ASAP usually represents either a small focus of carcinoma or one of its many mimics. COMMONLY USED IMMUNOHISTOCHEMICAL STAINS Basal Cell-Associated Markers In invasive prostate carcinoma, the basal cell layer is absent, so a complete absence of staining in basal cell-associated markers is supportive of a malignant interpretation. Under hematoxylin-eosin (H&E) microscopy, basal cells may be mimicked by prostatic stromal cells juxtaposed to the glandular-basement membrane, by endothelial cells of blood vessels closely situated to acini, and by tangentially sectioned neoplastic cells. Basal cell-associated markers highlight basal cells present in benign prostate glands and related benign, but architecturally atypical, proliferations (Figure 1, A through D). High-Molecular-Weight Cytokeratin 34[beta]E12.--Highmolecular-weight cytokeratin (HMCK) 34[beta]E12 is a cytoplasmic marker that highlights intermediate cytokeratin (CK) filaments in glandular basal cells and is specific for basal cells in the prostate. The monoclonal antibody clone 34BE12 (also known as CK903), which targets CK1, CK5, CK10, and CK14, is the time-honored basal cell marker used since 1985. (8) Although extended formalin fixation may affect 34[beta]E12 antigenicity, that can usually be restored with appropriate antigen-retrieval techniques. Staining with HMcK 34[beta]E12 can, however, vary between glands of a benign glandular proliferation and the staining pattern may not be circumferential. Although this was the first prostatic marker available in the differential diagnosis of cancer versus atypical benign glands, it has been our recent experience from cases seen in consultation that most laboratories do not use this marker in isolation but more commonly use it in combination with prostate cancer-specific marker a-methylacyl coenzyme A (coA) racemase (AMACR) or with other basal cell-associated markers. CK5/6--Another HMCK is CK5/6. (9-10) The overall sensitivity, specificity, and diagnostic utility of CK5/6 in prostate needle biopsies are similar to HMCK 34[beta]E12, and recently, a commercially available cocktail has substituted this antibody for 34[beta]E12. Similar results are obtained with antibodies to CK14. (10) p63.--This antibody targets the p63 nuclear protein, which is homologous to the TP53 tumor suppressor gene and has been proven to selectively stain the basal cell nuclei. (11) p63 is comparable to HMCK in sensitivity and specificity in needle biopsies, (11) although some studies have suggested that p63 has better sensitivity than HMCK 34[beta]E12 in specimens from transurethral resections of the prostate. (12) This differential staining may be related to alterations in antigenicity of basal cells in glands of benign prostatic hyperplasia. p63 immunostaining provides greater specificity because of its nuclear localization; the cytoplasmic staining to HMCK markers may have greater potential for nonspecific reaction. In our experience, p63 staining needs an intermediate power for evaluation because it selectively stains nuclei. We have seen nonspecific background cytoplasmic staining for p63 from more than the occasional laboratory, which may be due to improper antibody titration. Basal Cell-Associated Marker Cocktails.--Although use of a single basal cell-associated marker is sufficient for evaluation of most ASAP cases, the p63 and HMCK 34[beta]E12 or CK5/6 cocktail provide more intense positivity by highlighting both the nuclei and cytoplasm of basal cells. (13) The staining pattern is similar to HMCK 34[beta]E12, but the addition of p63 reduces staining variability seen within and between benign glands. Overall, the HMCK 34[beta]E12 and p63 cocktail offers only limited advantage in resolving individual atypical cases compared with each antibody used alone. (13) Thus, at this point, we recommend using any of these commonly available stains (HMCK 34[beta]E12, p63, and CK5/6, alone or in a combination cocktail) based on optimal staining reactions obtained in particular laboratories. [FIGURE 1 OMITTED] Recommended Interpretation Guidelines.--If basal cell-layer-associated makers alone are used, the diagnosis of carcinoma is made on a negative immunoreaction and, therefore, appropriate external and internal positive and negative controls must be used while interpreting the stain. Before evaluation of the immunohistochemical slide, all morphologically atypical glands must be identified by H&E, and the corresponding glands in the suspicious focus should be completely negative by immunohistochemistry. The consistency of the staining reaction should be confirmed in a second section on the same slide, if available. Potential Diagnostic Pitfalls.--Pitfalls in staining with basal cell-associated markers may be due to false negativity in benign mimics or false positivity in carcinoma and varies in the entities examined. In 5% to 23% of cases, scattered, obviously benign glands may show absent staining. (14) Staining may be weak-reactive to nonreactive in some benign proliferations that mimic cancer, such as in up to 23% of glandular atrophy, up to 50% of atypical adenomatous hyperplasia (AAH; adenosis), and 23% of post-atrophic hyperplasia. (14,15) Completely negative staining can occur in nonprostatic mimickers of carcinoma, such as in 44% to 75% of nephrogenic adenoma and 66% of mesonephric glandular hyperplasia. (14) There are rare scenarios in which prostate carcinoma may show immunoreactivity with basal cell markers, such as entrapped benign glands within carcinoma, cancerization of benign glands, intraductal cancer growth, ductal carcinoma of prostate, and high-grade prostatic carcinoma (especially at metastatic sites). Prostate Cancer-Associated Marker AMACR (P504S) The P504S gene was identified by combination of complementary DNA subtraction and high-throughput microarray to be overexpressed selectively by malignant, but not by benign, prostatic glands. (16-19) In subsequent studies of radical prostatectomies, specimens from transurethral resection of prostate and needle biopsies confirmed immunoreactive selectivity in malignant, but not benign, glands. The prostate carcinoma-associated AMACR positivity complements the lack of basal cell-associated staining in prostate carcinoma and thus safeguards from false-negativity associated with basal cell-related markers. Currently, AMACR is more commonly applied to complement basal cell markers in an antibody cocktail. a-Methylacyl coA racemase is seen in 75% to 95% of prostate carcinomas in diagnostic material staining observed across the spectrum of Gleason 5 to 10 carcinoma.14 The difference between the use of monoclonal (P504S) and polyclonal (pAMACR) antibody is marginal and clinically insignificant. (20) [FIGURE 2 OMITTED] Recommended Interpretation Guidelines.--To be interpreted as positive for carcinoma, AMACR should be circumferential, strong, and cytoplasmic, with a granular quality (Figure 2). (17) To be found positive, the staining of malignant glands must be stronger than adjacent benign acinar glands. Interpretation must always be in conjunction with H&E morphology and, preferably, with a basal cell stain. If there is a lot of background staining throughout the biopsy, staining should not be interpreted. Potential Diagnostic Pitfalls.--Positive AMACR staining does not always indicate carcinoma, and negative staining does not rule out carcinoma. Immunoreactivity to AMACR may be absent in 5% to 25% of typical prostate carcinomas. (14) Staining with AMACR varies in patterns of prostate carcinoma and can be negative in 30% of atrophic carcinoma, 32% to 38% of foamy gland carcinoma, and 23% to 30% of pseudohyperplastic carcinoma variants.21 Expression can be substantially diminished or completely lost in up to 29% of prostate carcinoma after hormonal therapy. (22) Conversely, reactivity with AMACR is seen in relatively higher proportions of premalignant proliferations, such as in 56% to 100% of high-grade prostatic intraepithelial neoplasia (PIN; in our experience, the range is closer to 50%) and 18% of AAH (Figure 3, A and B). (14) Occasionally, reactivity with AMACR can be seen in benign entities, such as in 35% to 58% of nephrogenic adenoma, 4% of atrophic carcinoma, and 2% to 36% of typical benign glands. (14) Finally, reactivity with AMACR can be seen in some secondary tumors involving the prostate, such as urothelial carcinoma and colonic adenocarcino ma. (23,24) Combination of Basal Cell-Associated Markers and AMACR The cocktail combining basal cell-associated markers and AMACR staining uses the opposite of the expected reaction for basal cell-associated markers and AMACR in benign and malignant prostate glands (Figures 2; 3, A and B; 4, B; 5, A through D). (25) The triple or PIN cocktail combines AMACR, p63, and HMCK using 2 chromogens: red for AMACR and brown for HMCK and p63. This 3-anti body, 2-chromogen cocktail has proven to be a simple and easy assay for routine use, and advantages include greater sensitivity for basal cells, including circumferential staining, easier detection of atypical acini (different-colored chromogen), and reducing the potential loss of representation from evaluating a single slide. (17,25) Studies have demonstrated that the antibody cocktail has been used to confirm carcinoma in 47% of ASAP diagnoses (Figure 4, A and B), (26) which depends, obviously, on the experience of the pathologist and the frequency with which the stain is ordered. Epithelial Markers The cocktail of AE1 and AE3 detects acidic (CK10, CK14-16, and CK19) and basic (CK1-CK6 and CK8) cytokeratins and is the most universally used epithelial marker. Cytokeratin AE1/AE3 is useful in the differential diagnosis of nonspecific granulomatous prostatitis, crushed or marked inflammation, or xanthoma cells versus high-grade prostate cancer with an infiltrative individual cell pattern (Gleason pattern 5; Table 5). Cytokeratin AE1/AE3 is also helpful in diagnosing small cell proliferations involving the prostate (differential diagnosis for small cell carcinoma, lymphoma, and rhabdomyosarcoma). In the posttreatment setting, CK AE1/AE3 is helpful in highlighting individual atrophic prostate cancer cells (27) and is superior to PSA, which can be suppressed by therapy and is, therefore, not detectable by immunohistochemistry following treatment. Prostate Lineage-Specific Markers Within the prostate gland, PSA and prostate-specific acid phosphatase (PSAP) are used to confirm a prostatic acinar cell origin and are useful in ruling out nonprostatic carcinoma mimics, such as seminal vesicle/ejaculatory duct, hyperplastic mesonephric glands, nephrogenic adenoma, Cowper glands, and paraganglionic tissue. (28) Another recent immunohistochemical marker for this purpose is prostate-specific membrane antigen, but there are few studies to date with this antibody. (29) Another use of PSA and PSAP is in the differential diagnosis of unusual variants of prostate carcinoma (ie, ductal, mucinous, and signet ring carcinoma), which stain positive for PSA and PSAP, versus secondary tumors involving the prostate (such as bladder or colonic adenocarcinomas), which are typically negative. Potential Diagnostic Pitfalls.--Prostate-specific antigen expression can be weak and focal in poorly differentiated prostate carcinoma. (28) The polyclonal PSA antibody may show occasional reactivity in up to 32% of normal, seminal vesicles; that staining is not seen with the monoclonal antibody. (28) Rare, weak PSA and PSAP positivity may be seen in nephrogenic adenoma. (30) [FIGURE 3 OMITTED] [FIGURE 4 OMITTED] DIAGNOSTIC SCENARIOS IN THE PROSTATE NEEDLE CORE BIOPSY: A MORPHOLOGIC PATTERN-BASED APPROACH Atypical Small Acinar Proliferation Atypical small acinar proliferation is the most frequent indication found by immunohistochemistry in prostate needle biopsies. Atypical small acinar proliferation is not a diagnostic entity but is a descriptive diagnosis rendered when there is quantitatively or qualitatively insufficient criteria for the diagnosis of carcinoma. (31,32) Another scenario in which an ASAP diagnosis may be rendered is when the glands are closely related to glands of high-grade PIN, in such a way that outpouching of the PIN glands cannot be reliably differentiated from glands of early, invasive carcinoma. Not all ASAP glands are worthy of immunohistochemistry, and the central question to be addressed before immunohistochemistry is ordered is whether immunohistochemical staining patterns will influence the diagnosis. Ordering immunohistochemistry prospectively is not necessary in all cases of prostatic needle biopsies (Figures 6, A and B). There are 2 potential reasons for performing immunohistochemistry in the ASAP setting: to obtain further evidence of carcinoma, and to rule out potential mimics. Atypical small acinar proliferation in a closely associated spatial arrangement with high-grade PIN does not, in our opinion, always merit immunohistochemical evaluation because the immunohistochemical reaction will not necessarily influence our ability to designate the ASAP glands as cancer; the presence of a basal cell layer around the atypical glands, as suggested by immunohistochemistry, can, however, forestall a diagnosis of invasive carcinoma. The key immunostains for this scenario are basal cell-associated markers and AMACR used separately or in a cocktail. The expected reactions in the differential diagnosis of ASAP are shown in Table 3. One study (33) demonstrated that benign glands are never simultaneously positive for AMACR and negative for basal cell markers (100% specificity), which has also been our experience to date. Even if carcinoma is diagnosed in one core, the presence of ASAP in another core from a separate site may still require immunohistochemical workup if the additional focus would clinically upstage the tumor, for example, if ASAP is on the opposite side (pT2a vs pT2b). Furthermore, although the criteria for watchful waiting in a patient with confirmed cancer are still evolving, the number of positive cores may influence the decision in this setting, so it may be important to further characterize ASAP foci with immunohistochemistry. [FIGURE 5 OMITTED] Atypical Large Glandular Proliferations It is well established that glands of high-grade PIN, invasive small acinar adenocarcinoma, and intraductal extension of adenocarcinoma form a morphologic continuum that may be better appreciated in prostatectomy specimens. (34) Also, prostatic ductal carcinomas, which have a large glandular morphology, can have intraductal growth and coexist with invasive carcinoma of the usual type. (35) In needle biopsies, these distinctions may not be easy to differentiate, especially in the absence of obvious invasive cancer. Invasive ductal carcinoma is diagnosed if there is back-to-back complex growth of large glandular structures with cribriform or papillary architecture with true papillae and marked nuclear atypia. High-grade PIN is composed of medium to large glands that show normal spatial arrangement between the glands and that contain atypical nuclei, sometimes with maturation toward the lumen. In limited representation of atypical large glands without obvious invasive growth, immunohistochemistry can be of value. High-grade PIN may express AMACR and can show the presence of a basal cell layer. For diagnoses of invasive ductal adenocarcinoma from needle biopsies with limited glands, there needs to be a complete absence of the basal cell layer around all, or most of, the atypical acini. The expected reactions in the differential diagnosis of atypical large glandular proliferations are shown in Table 4. In this differential diagnostic setting, greater weight is given to the basal cell-associated markers because AMACR is commonly expressed by most entities within the differential group. A recent study has shown that 31% of ductal and 30% of cribriform prostatic carcinoma can have residual basal cells, and 27% of ductal and 37% of cribriform prostatic carcinoma do not express AMACR. (36) Thus, H&E assessment remains critical in the diagnosis of these lesions and caution should be exercised when only few large glandular structures are present (Figures 6, C and D). Single Individual Cell Patterns and Posttreatment Carcinoma The expected reaction in the differential diagnosis of a single individual cell pattern is shown in Table 5. Our recommended panel in the posttreatment setting is CK AE1/AE3, with the triple cocktail of AMACR, p63, and HMCK 34[beta]E12 or CK5/6. Cytokeratin AE1/AE3 highlights subtle carcinoma cells with marked treatment effect and can provide a better estimate of cancer burden in the needle biopsy. [alpha]-Methylacyl coA racemase expression is directly proportional to the severity of the therapy effect and may not be helpful in cases with a marked effect.17 The use of proliferation markers to assess tumor viability is considered experimental at this point, but may be ordered, based on the institutional preference of the pathologists and treating physicians. [FIGURE 6 OMITTED] Other Unusual Situations When we see what appears to be prostatic carcinoma with an unusual morphology, such as seen in atrophic carcinoma, (37) pseudohyperplastic carcinoma, (38) or carcinoma with a double layer,39 we usually use immunohistochemical stains for cancer confirmation, unless there is an accompanying prostate cancer tumor with a more typical histology. In prostatic biopsies that show extensive, infiltrating, poorly differentiated carcinoma, the differential diagnosis for a prostatic, versus urothelial, primary tumor may require the use of immunohistochemistry. In this setting, our recommended panel includes PSA and PSAP (which are expected to be positive for prostate cancer and negative for urothelial carcinoma) and HMCK and p63 (which are expected to be negative for prostate cancer and positive for urothelial carcinoma in 65%-100% and 70%-75% of specimens, respectively). (40,41) If that panel does not prove conclusive, our second line of antibodies includes thrombomodulin (which is positive in 49%-69% of urothelial carcinoma specimens) and CD57. (41-42) Aberrant nuclear expression of p63 in prostate carcinoma has been reported recently43; hence, the use of a panel of tests is crucial to avoiding misdiagnosis from this rare phenomenon. Cowper glands, hyperplasia of mesonephric remnants, and nephrogenic adenoma can all be negative for HMCK (44-46); the morphologic and immunohistochemical overlap is further confounded in nephrogenic adenoma, which can be positive for AMACR. (47) If nonprostatic glandular mimics are not considered morphologically in the differential diagnosis, those lesions represent significant diagnostic pitfalls, and the immunohistochemistry results can, potentially, compound the difficulty. Prostate-specific antigen and PSAP provide confirmation for the nonprostatic lineage of these mimics (Table 6). SUMMARY The availability of basal cell-associated markers, prostate cancer-associated marker AMACR, and prostate lineage-specific markers PSA and PSAP provide significant, objective evidence in confirming whether glandular lesions are benign or malignant and whether they are of prostatic origin. Although these markers provide invaluable ancillary diagnostic assistance, the myriad differential diagnostic considerations and overlapping staining reactions mean that the final diagnosis must reflect the context and be correlated with the original H&E-derived diagnosis. We recommend an immunohistochemical panel approach based on the differential diagnostic scenario as the best practice for distinguishing prostate cancer and its mimics in needle core biopsies. References (1.) Srigley JR. Benign mimickers of prostatic adenocarcinoma. Mod Pathol. 2004;17:328-348. (2.) Herawi M, Parwani AV, Irie J, Epstein JI. Small glandular proliferations on needle biopsies: most common benign mimickers of prostatic adenocarcinoma sent in for expert second opinion. Am J Surg Pathol. 2005;29:874-880. (3.) Amin M, Beach R, Gown AM, et al. Use of a novel immunohistochemical (IHC) panel (P504S, p63 and 34BE12) in the diagnosis of post-radiation therapy (PRT) prostate cancer (PCa). Mod Pathol. 2003;16:139A. (4.) Bates AW, Baithun SI. Secondary solid neoplasms of the prostate: a clinico-pathological series of 51 cases. Virchows Arch. 2002;440:392-396. (5.) Chuang AY, DeMarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI. Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma. Am J Surg Pathol. 2007;31:1246-1255. (6.) Osunkoya AO, Netto GJ, Epstein JI. Colorectal adenocarcinoma involving the prostate: report of 9 cases. Hum Pathol. 2007;38:1836-1841. (7.) Green R, Epstein JI. Use of intervening unstained slides for immunohistochemical stains for high molecular weight cytokeratin on prostate needle biopsies. Am JSurgPathol. 1999;23:567-570. (8.) Wojno KJ, Epstein JI. The utility of basal cell-specific anti-cytokeratin antibody (34[beta]E12) in the diagnosis of prostate cancer: a review of 228 cases. Am J Surg Pathol. 1995;19:251-260. (9.) Abrahams NA, Ormsby AH, Brainard J. Validation of cytokeratin 5/6 as an effective substitute for keratin 903 in the differentiation of benign from malignant glands in prostate needle biopsies. Histopathology. 2002;41:35-41. (10.) Reis-Filho JS, Simpson PT, Martins A, Preto A, Gartner F, Schmitt FC. Distribution of p63, cytokeratins 5/6 and cytokeratin 14 in 51 normal and 400 neoplastic human tissue samples using TARP-4 multi-tumor tissue microarray. Virchows Arch. 2003;443:122-132. (11.) Weinstein MH, Signoretti S, Loda M. Diagnostic utility of immunohistochemical staining for p63, a sensitive marker ofprostatic basal cells. Mod Pathol. 2002;15:1302-1308. (12.) Shah RB, Zhou M, LeBlanc M, Snyder M, Rubin MA. Comparison of the basal cell-specific markers, 34|3E12 and p63, in the diagnosis of prostate cancer. Am J Surg Pathol. 2002;26:1161-1168. (13.) Shah RB, Kunju LP, Shen R, LeBlanc M, Zhou M, Rubin MA. Usefulness of basal cell cocktail (34|3E12 + p63) in the diagnosis of atypical prostate glandular proliferations. Am J Clin Pathol. 2004;122:517-523. (14.) Hameed O, Humphrey PA. Immunohistochemistry in diagnostic surgical pathology of the prostate. Semin Diagn Pathol. 2005;22:88-104. (15.) Amin MB, Tamboli P, Varma M, Srigley JR. Postatrophic hyperplasia of the prostate gland: a detailed analysis of its morphology in needle biopsy specimens. Am J Surg Pathol. 1999;23:925-931. (16.) Jiang Z, Woda BA, Rock KL, et al. P504S: a new molecular marker for the detection of prostate carcinoma. Am J Surg Pathol. 2001;25:1397-1404. (17.) Beach R, Gown AM, De Peralta-Venturina MN, et al. P504S immunohistochemical detection in 405 prostatic specimens including 376 18-gauge needle biopsies. Am J Surg Pathol. 2002;26:1588-1596. (18.) Jiang Z, Wu CL, Woda BA, et al. P504S/alpha-methylacyl-CoA racemase: a useful marker for diagnosis of small foci of prostatic carcinoma on needle biopsy. Am J Surg Pathol. 2002;26:1169-1174. (19.) Jiang Z, Woda BA. Diagnostic utility of a-methylacyl CoA racemase (P504S) on prostate needle biopsy. Adv Anat Pathol. 2004;11:316-321. (20.) Kunju LP, Chinnaiyan AM, Shah RB. Comparison of monoclonal antibody (P504S) and polyclonal antibody to a-methylacyl-CoA racemase (AMACR) in the work-up of prostate cancer. Histopathology. 2005;47:587-596. (21.) Varma M, Jasani B. Diagnostic utility of immunohistochemistry in morphologically difficult prostate cancer: review of current literature. Histopathology. 2005;47:1-16. (22.) Sung MT, Jiang Z, Montironi R, Maclennan GT, Mazzucchelli R, Cheng L. a-Methylacyl-CoA racemase (P504S)/34|3E12/p63 triple cocktail stain in prostatic adenocarcinoma after hormonal therapy. Hum Pathol. 2007;38:332-341. (23.) Zhou M, Chinnaiyan AM, Kleer CG, Lucas PC, Rubin MA. a-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions. Am J SurgPathol. 2002;26:926-931. (24.) Nassar A, Amin MB, Sexton DG, Cohen C. Utility of a-methylacyl coenzyme A racemase (p504s antibody) as a diagnostic immunohistochemical marker for cancer. Appl Immunohistochem Mol Morphol. 2005;13:252-255. (25.) Hameed O, Sublett J, Humphrey PA. Immunohistochemical stains for p63 and a-methylacyl-CoA racemase, versus a cocktail comprising both, in the diagnosis of prostatic carcinoma: a comparison ofthe immunohistochemical staining of 430 foci in radical prostatectomy and needle biopsy tissues. Am J Surg Pathol. 2005;29:579-587. (26.) Molinie V, Fromont G, Sibony M, et al. Diagnostic utility of a p63/a-methyl-CoA-racemase (p504s) cocktail in atypical foci in the prostate. Mod Pathol. 2004;17:1180-1190. (27.) Bazinet M, Zheng W, Begin LR, Aprikian AG, Karakiewicz PI, Elhilali MM. Morphologic changes induced by neoadjuvant androgen ablation may result in under detection of positive surgical margins and capsular involvement by prostatic adenocarcinoma. Urology. 1997;49:721-725. (28.) Varma M, Morgan M, Jasani B, Tamboli P, Amin MB. Polyclonal anti-PSA is more sensitive but less specific than monoclonal anti-PSA: implications for diagnostic prostatic pathology. Am J Clin Pathol. 2002;118:202-207. (29.) Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. 1998;82:2256-2261. (30.) Allan CH, Epstein JI. Nephrogenic adenoma of the prostatic urethra: a mimicker of prostate adenocarcinoma. Am J Surg Pathol. 2001;25:802-808. (31.) Bostwick DG, Meiers I. Atypical small acinar proliferation in the prostate: clinical significance in 2006. Arch Pathol Lab Med. 2006;130:952-957. (32.) Iczkowski KA. Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains. Arch Pathol Lab Med. 2006;130:835-843. (33.) Jiang Z, Li C, Fischer A, Dresser K, Woda BA. Using an AMACR (P504S)/ 34[beta]E12/p63 cocktail for the detection of small focal prostate carcinoma in needle biopsy specimens. Am J Clin Pathol. 2005;123:231-236. (34.) Cohen RJ, Wheeler TM, Bonkhoff H, Rubin MA. A proposal on the identification, histologic reporting, and implications of intraductal prostatic carcinoma. Arch Pathol Lab Med. 2007;131:1103-1109. (35.) Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical significance. Mod Pathol. 2006;19:1528-1535. (36.) Herawi M, Epstein JI. Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate. Am J Surg Pathol. 2007;31:889-894. (37.) Przybycin CG, Kunju LP, Wu AJ, Shah RB. Partial atrophy in prostate needle biopsies: a detailed analysis of its morphology, immunophenotype, and cellular kinetics. Am J Surg Pathol. 2008;32:58-64. (38.) Zhou M, Jiang Z, Epstein JI. Expression and diagnostic utility of [alpha]-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer. Am J Surg Pathol. 2003;27:772-778. (39.) Hameed O, Humphrey PA. Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia. Mod Pathol. 2006;19:899-906. (40.) McKenney JK, Amin MB. The role of immunohistochemistry in the diagnosis of urinary bladder neoplasms. Semin Diagn Pathol. 2005;22:69-87. (41.) Parker DC, Folpe AL, Bell J, et al. Potential utility of uroplakin III, thrombomodulin, high molecular weight cytokeratin, and cytokeratin 20 in noninvasive, invasive, and metastatic urothelial (transitional cell) carcinomas. Am J Surg Pathol. 2003;27:1-10. (42.) Genega EM, Hutchinson B, Reuter VE, Gaudin PB. Immunophenotype of high-grade prostatic adenocarcinoma and urothelial carcinoma. Mod Pathol. 2000;13:1186-1191. (43.) 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;32:461-467. (44.) Saboorian MH, Huffman H, Ashfaq R, AyalaAG, RoJY. Distinguishing Cowper's glands from neoplastic and pseudoneoplastic lesions of prostate: immunohistochemical and ultrastructural studies. Am J Surg Pathol. 1997;21:1069-1074. (45.) Bostwick DG, Qian J, Ma J, Muir TE. Mesonephric remnants of the prostate: incidence and histologic spectrum. Mod Pathol. 2003;16:630-635. (46.) Malpica A, Ro JY, Troncoso P, Ordonez NG, Amin MB, Ayala AG. Nephrogenic adenoma of the prostatic urethra involving the prostate gland: a clinicopathologic and immunohistochemical study of eight cases. Hum Pathol. 1994; 25:390-395. (47.) Skinnider BF, Oliva E, Young RH, Amin MB. Expression of a-methylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocar cinoma. Am J Surg Pathol. 2004;28:701-705. Gladell P. Paner, MD; Daniel J. Luthringer, MD; Mahul B. Amin, MD Accepted for publication May 16, 2008. From the Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif. Dr Paner is now located at Loyola University Medical Center, Maywood, Ill. The authors have no relevant financial interest in the products or companies described in this article. This article is provided for educational purposes only and is not intended to suggest either a practice standard or the only acceptable pathway for diagnostic evaluation. The views presented reflect the authors' opinions. The application of these opinions to a particular medical situation must be guided by the informed medical judgment of the responsible pathologist(s) based on the individual circumstances presented by the patient. The College of American Pathologists has no responsibility for the content or application of the views expressed herein. Reprints: Mahul B. Amin, MD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite 8728, Los Angeles, CA 90048 (e-mail: aminm@cshs.org). Table 1. Morphology-Based Differential Diagnoses for Prostate
Carcinoma in Needle Biopsies *
Histologic Pattern Prostate Carcinoma
ASAP Glandular Gleason pattern 3
Atrophic pattern
Posttreatment cancer
Atypical large glandular Cribriform Gleason patterns 3, 4, and 5
proliferation Ductal adenocarcinoma
Pseudohyperplastic pattern
Infiltrative single Gleason pattern 5
cell pattern Posttreatment carcinoma
Clear cell pattern Hypernephroid Gleason pattern 4
Glandular Gleason pattern 3
Oncocytic pattern Gleason pattern 4
Poorly to undifferentiated Solid Gleason pattern 5
carcinoma
Spindle cell pattern Sarcomatoid carcinoma
Histologic Pattern Main Differential Diagnoses
ASAP Crowded benign glands, NOS
Atrophy
Outpouching of high-grade PIN
AAH (adenosis)
Sclerosing adenosis
Basal cell hyperplasia
Postatrophic hyperplasia
Seminal vesicle epithelium
Ejaculatory duct
Cowper glands
Mesonephric remnants
Nephrogenic adenoma
Verumontanum mucosal gland hyperplasia
Radiation atypia
Atypical large glandular High-grade PIN
proliferation Urothelial carcinoma involving
prostatic ducts and acini
Colorectal carcinoma involving prostate
Clear cell cribriform hyperplasia
Squamous metaplasia
Urothelial metaplasia
Infiltrative single Dense inflammation
cell pattern Granulomatous prostatitis
Lymphoma
Small cell carcinoma
Clear cell pattern Prostatic xanthoma
Oncocytic pattern Paraganglion/paraganglioma
Carcinoid tumor
Poorly to undifferentiated Urothelial carcinoma
carcinoma
Spindle cell pattern Pseudosarcomatous myofibroblasts
proliferations
Stromal sarcoma
Leiomyosarcoma
* ASAP indicates atypical small acinar proliferation; NOS, not
otherwise specified; PIN, prostatic intraepithelial neoplasia; and
AAH, atypical adenomatous hyperplasia.
Table 2. Important Immunohistochemical Stains in the Diagnosis of
Prostate Carcinoma *
Immunostains Rationale for Use
Basal cell-associated markers Benign vs malignant
HMCK 34[beta]E12 proliferation--absence of the
CK5/6 basal cell layer is the defining
p63 criterion for invasive prostate
Basal cell cocktail carcinoma
Prostate carcinoma-associated marker Benign vs malignant
AMACR/p504S proliferation--expression
favoring neoplastic
transformation
Antibody cocktails Benign vs malignant
AMACR/p63/HMCK 340E12 proliferation--absence of basal
AMACR/p63/CK5/6 cell-associated markers and
AMACR/p63 presence of prostate carcinoma-
associated marker favoring
invasive prostate carcinoma
Epithelial lineage Identification of subtle
CK AE1/AE3 infiltrating cells in
posttreatment setting; in the
differential diagnosis of
carcinoma vs nonepithelial
process or malignancy
Prostate lineage-specific marker Prostatic vs nonprostatic
PSA origin, eg, Cowper gland,
PSAP mesonephric remnant, nephrogenic
adenoma, seminal vesicle
* HMCK indicates high-molecular-weight cytokeratin; CK,
cytokeratin; basal cell cocktail, p63/HMCK 34BE12 or p63/CK5/6;
AMACR, [alpha]-methylacyl coenzyme A racemase; PSA, prostate-specific
antigen; and PSAP, prostatic acid phosphatase.
Table 3. Expected Immunoreactivity in Atypical
Glandular Proliferations *
Basal Cell-Associated
Differential Diagnosis Markers AMACR
Benign glands including
atrophy, postatrophic
hyperplasia, etc + -
Prostate carcinoma - +
AAH (adenosis) +/- (patchy) - /+
Basal cell hyperplasia + -
* AMACR indicates a-methylacyl coenzyme A racemase; +,
positive; -, negative; and AAH, atypical adenomatous hyperplasia.
Table 4. Expected Immunoreactivity in Select Large
Glandular Proliferations *
Basal Cell
Differential Diagnosis Marker AMACR
Cribriform Gleason patterns 3, 4, and 5 - +
Ductal adenocarcinoma - /+ +
High-grade PIN + +/-
Carcinoma with intraductal growth + +
Squamous and urothelial metaplasia + -
* AMACR indicates a-methylacyl coenzyme A racemase; -,
negative; +, positive; and PIN, prostatic intraepithelial neoplasia.
Table 5. Expected Immunoreactivity in Single-Individual
Cell Patterns *
CK Basal Cell
Differential Diagnosis AE1/AE3 Marker AMACR
Gleason pattern 5 prostate
carcinoma + - +
Posttreatment carcinoma + - +/-
Marked inflammation - - ([dagger]) - ([dagger])
Granulomatous prostatitis - - ([dagger]) - ([dagger])
* CK indicates cytokeratin; AMACR, [alpha]-methylacyl coenzyme
A racemase; +, positive; and -, negative.
([dagger]) Not indicated if keratin is negative.
Table 6. Expected Immunoreactivity in Benign
Mimickers of Prostate Carcinoma *
PSA/ Basal Cell
Differential Diagnosis PSAP Marker
Seminal vesicle/ejaculatory
duct - /+ ([dagger]) + (basal cell)
Cowper gland - -/+
Mesonephric remnants - -/+
Nephrogenic adenoma - /+ ([dagger]) -/+
Differential Diagnosis AMACR
Seminal vesicle/ejaculatory
duct - ([double dagger])
Cowper gland -
Mesonephric remnants -
Nephrogenic adenoma +/-
* PSA indicates prostate-specific antigen; PSAP, prostatic acid
phosphatase; AMACR, [alpha]-methylacyl coenzyme A racemase; -,
negative; and +, positive.
([dagger]) 36% positive with polyclonal antibody.
([double dagger]) Corresponds to nonspecific staining in
lipofuscin pigment. |
| Gale Copyright: | Copyright 2008 Gale, Cengage Learning. All rights reserved. |
Previous Article: Analysis of pathology department web sites and
practical recommendations.
Next Article: Correction.
Next Article: Correction.