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American Journal of Surgical Pathology:
doi: 10.1097/PAS.0000000000000238
Special Articles

Best Practices Recommendations in the Application of Immunohistochemistry in the Prostate: Report From the International Society of Urologic Pathology Consensus Conference

Epstein, Jonathan I. MD*; Egevad, Lars MD, PhD; Humphrey, Peter A. MD, PhD; Montironi, Rodolfo MD§; Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group

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Author Information

*Departments of Pathology, Urology, and Oncology, The John Hopkins Medical Institutions, Baltimore, MD

Department of Pathology, Yale University School of Medicine, New Haven, CT

Department of Oncology–Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

§Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy

Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group: Mahul B. Amin, Thomas M. Ulbright, David Grignon, Kiril Trpkov, Antonio Lopez-Beltran, Ming Zhou, Pedram Argani, Brett Delahunt, Daniel M. Berney, John R. Srigley, Satish K. Tickoo, Victor E. Reuter.

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Jonathan I. Epstein, MD, Departments of Pathology, Urology, and Oncology, The John Hopkins Medical Institutions, The Weinberg Building, Rm. 2242 40l N. Broadway Street, Baltimore, MD 21231 (e-mail: jepstein@jhmi.edu).

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Abstract

The following are the International Society of Urological Pathology (ISUP) recommendations for the use of immunohistochemistry (IHC) in prostate specimens. Either high–molecular weight cytokeratin (34βE12 or CK5/6 or others) or p63 or a combination of the 2 with AMACR either in a double or triple cocktail is recommended for the workup of small foci of atypical glands suspicious for adenocarcinoma of the prostate (PCa). ERG is optional as it is present in only 40% to 50% of prostate cancers and also positive in high-grade prostatic intraepithelial neoplasia. In the setting of obvious carcinoma or benign glands, there is no justification to do basal cell stains and AMACR. If there is a Gleason score of 3+4=7 or a higher-grade cancer on at least 1 part, the workup of other parts with an atypical focus suspicious for Gleason score 3+3=6 cancer is not recommended. In the setting of Gleason score 4+3 or 4+4=8 cancer on at least 1 part, the extent of high-grade cancer could affect clinical treatment such that workup of other atypical possible high-grade cancer foci is justified. In the setting of Gleason score 4+3 or higher-grade cancer on at least 1 part, given that intraductal carcinoma in the vast majority of cases is considered extension of high-grade cancer into prostatic ducts and acini, it is not recommended in the setting of definitive invasive high-grade cancer that workup of additional cribriform lesions be pursued. In the setting of Gleason score 3+3 on at least 1 part, the number of positive cores and/or their location could possibly affect subsequent therapy in terms of suitability for active surveillance or focal therapy, such that unless one knows with certainty that it would not affect therapy, it is justified to perform an IHC workup of additional atypical foci. In the differential diagnosis of high-grade PCa versus urothelial carcinoma (UC), the primary option is to use prostate-specific antigen (PSA) as a first test to identify PCa and GATA3 to identify UC. If GATA3 is not available, then HMWCK and p63 can be used. If the tumor is PSA positive with intense staining and HMWCK and p63 negative, the findings are diagnostic of PCa. If the tumor is equivocal/weak/negative for PSA and negative/focal for p63 and HMWCK, then one needs to perform staining for P501S, NKX3.1, and GATA3. Some experts also include PAP in this second round of staining. If the tumor is negative for PSA and diffusely strongly positive for p63 and HMWCK, the findings are diagnostic of UC. If the tumor is negative for PSA and moderately to strongly positive for GATA3, it is diagnostic of UC. Laboratories should be encouraged to use GATA3 for UC and add P501S and NKX3.1 as prostate markers in addition to PSA, p63, and HMWCK. If GATA3, p501S, and NKX3.1 are not available in equivocal cases, the case should be sent out for consultation to laboratories with these antibodies. The article also covers the use of IHC in: (1) high-grade PCa versus bladder adenocarcinoma; (2) prostatic small cell carcinoma versus high-grade PCa; (3) metastatic carcinoma of unknown primary: rule out PCa; (4) nonspecific granulomatous prostatitis/xanthoma versus high-grade PCa; (5) adult prostate sarcoma versus sarcomatoid PCa; (6) colorectal adenocarcinoma versus high-grade PCa; and (7) prognostic IHC markers.

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IMMUNOHISTOCHEMICAL PANEL FOR THE DIAGNOSIS OF LIMITED PROSTATE ADENOCARCINOMA ON NEEDLE BIOPSY

Probably the most common use of immunohistochemistry (IHC) in the evaluation of the prostate is for the identification of basal cells, which are absent with rare exception in adenocarcinoma of the prostate (PCa). Although typically benign glands are positive for basal cells with IHC, adenosis, partial atrophy, and high-grade prostatic intraepithelial neoplasia (HGPIN) can have very patchy or absence of basal cells in a focus on needle biopsy (Figs. 1A–D). The most commonly used basal cell antibodies are high–molecular weight cytokeratin (HMWCK) (34βE12, cytokeratin [CK] 5/6)1–6 and p63,7–9 which are cytoplasmic and nuclear antibodies, respectively. p40 which is an isoform of p63 shows less aberrant p63 immunoreactivity in PCa but also has more nonspecific cytoplasmic staining compared with p63. In general p63 and p40 are comparable.10

Figure 1
Figure 1
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Several studies comparing HMWCK and p63 have showed p63 to be slightly superior.7,8 One study demonstrated that CK5/6 was superior to 34βE12, although only a minority of pathologists use CK5/6.11 The use of a double cocktail combining HMWCK and p63 can increase the sensitivity of basal cell detection with a decrease in staining variability.12–14 There are uncommon cases of acinar adenocarcinoma that label positive with HMWCK and less so with p63 in a non–basal cell distribution. This phenomenon, although more commonly encountered in high-grade acinar adenocarcinoma (Gleason score of 8 to 10), has sometimes been reported in small foci of adenocarcinoma of Gleason pattern 3 on needle biopsies (Figs. 1E, F, 2A).15 Aberrant diffuse expression of p63 in acinar adenocarcinoma is a recently recognized phenomenon (Fig. 2B).15–17 These cases differ from those showing the nonspecific staining of basal cell markers in adenocarcinoma described above in 3 major aspects: (1) staining for p63 is strong and diffuse within the malignant glands; (2) the majority of cases with aberrant p63 show distinctive morphology of infiltrative glands, nests and cords with atrophic cytoplasm, hyperchromatic nuclei, and visible nucleoli; and (3) other basal cell markers such as 34βE12 and CK5/6 are totally negative.

Figure 2
Figure 2
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α-Methylacyl-CoA-racemase (AMACR) is significantly upregulated in prostate cancer. Antibodies (P504S) have been developed against this protein.12,18–20 By IHC, the majority of prostate cancers are positive for AMACR, the sensitivity varying among studies from 82% to 100%.20–26 Two studies have shown that if a case is still considered atypical by a uropathology expert after negative basal cell staining, positive staining for AMACR can help establish in 50% of these cases a definitive diagnosis of cancer.27,28 There does not appear to be a difference between polyclonal and monoclonal P504s in the sensitivity of labeling prostate cancer.29

Different cocktails have been investigated combining antibodies for AMACR and basal cell–specific markers. One combination is with antibodies to p63 and AMACR, both labeled with a brown chromogen.30–32 Although authors have reported that this cocktail is essentially equal to each antibody used separately, in our experience a problem with this cocktail is that in some cases focal nuclear staining for p63 can be hard to detect if the cytoplasmic staining for AMACR is intensely positive. With small foci of atypical glands, the lesion may not survive sectioning to perform separate staining analyses for basal cell markers and AMACR on different slides.33 A triple-stain cocktail using a brown chromogen for both HMWCK and p63 and a red chromogen for AMACR optimizes the preservation of tissue for IHC and has been shown to be better than basal cell markers by themselves (Figs. 2C, D).34 In North America, there was a change in reimbursement for a triple stain containing 3 antibodies to the same as for 1 antibody, leading many laboratories that once used the triple stain to revert to 3 separate stains. Starting in January 2014, payers in the United States will revert to allowing payment for the 3 antibodies of a triple cocktail, although 2 antibodies will be compensated at a reduced rate. In cases in which there is no more tissue within the paraffin block and there are at least 2 hematoxylin and eosin (H&E) sections with the lesion, a technique has been developed to transfer tissue from one of the H&E slides to charged slides so that triple staining can be performed; an equivalent sensitivity compared with performing IHC off of the paraffin block can be achieved.35

The latest marker that has been proposed as an aid to the diagnosis of limited PCa is ERG. Fusions between the androgen-regulated transmembrane protease serine 2 gene (TMPRSS2) and the ERG gene are present in approximately 40% to 50% of PCas. This gene fusion is highly specific for prostate cancer, with the exception that 16% to 20% of HGPIN also shows the gene fusion. TMPRSS2-ERG gene fusion monoclonal anti-ERG antibodies are available, which correlate well with fusion-positive cancer. ERG antibodies have been shown to be negative in postatrophic hyperplasia, partial atrophy, and adenosis.36–38 Rare benign glands can express ERG.36,39 As an internal control, ERG labels endothelium. The major limitation of ERG as a diagnostic test is its low sensitivity, in that a negative stain does not exclude prostate carcinoma. Another weakness of this marker is that in 16% to 28% of cancers, there is heterogenous ERG expression, further contributing to false-negative staining on biopsy.40–43 In 16% to 20% of cases that are ERG positive, staining is also weak.40,44 Cocktails have also been developed for p63/ERG and ERG/AMACR/HMWCK/p63.40,44 There are conflicting studies on the diagnostic utility of ERG. Shah et al44 claimed that ERG helped establish a diagnosis of prostate cancer in 28% of cases that otherwise would have been diagnosed as “atypical, suspicious for carcinoma” using IHC for basal cell markers and AMACR. He et al,36 however, reported that ERG IHC was not discriminatory in helping to identify which “atypical foci” were likely to be associated with prostate cancer on rebiopsy. The advantages and disadvantages for the various antibodies for the diagnosis of limited PCa on needle biopsy are listed in Table 1.

Table 1
Table 1
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ISUP Recommendations

Either HMWCK (34βE12 or CK5/6 or others) or p63 or a combination of the 2 with AMACR either in a double or triple cocktail is recommended for the workup of small foci of atypical glands suspicious for PCa. ERG is optional as it is present in only 40% to 50% of prostate cancers and also positive in HGPIN.

In the setting of obvious carcinoma, there is no justification to perform basal cell and AMACR staining.

In the setting of obviously benign glands, there is no justification to perform basal cell and AMACR staining.

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WORKUP OF ATYPICAL FOCI WITH DEFINITE CANCER IN OTHER PARTS

Setting 1. Gleason score 3+4=7 or higher-grade cancer on at least 1 part: Workup of other parts with atypical foci suspicious for Gleason score 3+3=6 cancer.

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ISUP Recommendation

Unlikely to change clinical treatment so not recommended.

Setting 2. Gleason score 4+3 or 4+4=8 cancer on at least 1 part: Workup other parts with atypical small foci suspicious for the same grade cancer.

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ISUP Recommendation

The extent of high-grade cancer could affect clinical treatment such that workup of other atypical possible high-grade cancer foci is justified.

Setting 3. Gleason score 4+3 or higher-grade cancer on at least 1 part: Workup other parts for cribriform intraductal carcinoma versus diagnosing Gleason pattern 4 if doing so does not change the overall grade.

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ISUP Recommendation

Given that intraductal carcinoma in the vast majority of cases is considered an extension of high-grade cancer into prostatic ducts and acini, it is not recommended in the setting of definitive invasive high-grade cancer that workup of additional cribriform lesions be pursued.

Setting 4. Gleason score 3+3 on at least 1 part: Workup other parts for possible small foci of 3+3=6.

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ISUP Recommendation

The number of positive cores and/or their location could possibly affect subsequent therapy in terms of suitability for active surveillance or focal therapy, such that unless one knows with certainty that it would not affect therapy, it is justified to perform an IHC workup of additional atypical foci.

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POORLY DIFFERENTIATED PCA VERSUS UROTHELIAL CARCINOMA

The distinction between poorly differentiated urothelial carcinoma and poorly differentiated PCa, even in a metastatic site, is critical, as the 2 are treated very differently. Although the distinction between urothelial carcinoma and PCa can usually be made on routinely stained sections, there may be overlap in cases in which PCa has marked pleomorphism and even pseudopapillary structures mimicking urothelial carcinoma. Consequently, in a poorly differentiated tumor involving the bladder and prostate without any glandular differentiation typical of PCa, the case should be worked up immunohistochemically.

With only a few exceptions, IHC staining for prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) is very specific for prostatic tissue. Situations that can cause diagnostic difficulty include PSA and PSAP within periurethral glands, as well as cystitis cystica and cystitis glandularis in both men and women.45,46 Other examples of cross-reactive staining include anal glands in men (PSA, PSAP) and urachal remnants (PSA).47,48 Some intestinal carcinoids and pancreatic islet cell tumors are strongly reactive with antibodies to PSAP, yet are negative with antibodies to PSA.49 Periurethral gland carcinomas in women and various salivary gland tumors may also be PSA and PSAP positive.50,51 Weak false-positive staining for PSAP has been reported in several breast and renal cell carcinomas, and we have seen some cases in which PSA was focally and weakly positive, although the patient was subsequently shown to have a nonprostatic tumor. This suggests that weak focal positive staining for either antigen should be interpreted with caution.

Although PSA and PSAP have proven to be useful in identifying prostate lineage, their sensitivity decreases in poorly differentiated PCa. In 3 studies addressing this issue, <25% of the tumor cells stained with PSAP and PSA in 35% to 70% and 25% to 50% of the cases, respectively.52–54 The same studies found 5% to 13% of cases to be completely negative to PSAP or PSA. The significance of these figures is that given the at times limited amount of tissue sampled, up to 50% of the PCa may be interpreted as negative for PSA or PSAP, owing to only focal positivity that may not be sampled. Even when both PSA and PSAP are used, the lack of immunoreactivity in a poorly differentiated tumor within the prostate, especially on a limited amount of sample, does not exclude the diagnosis of a poorly differentiated PCa. In such a scenario, newer prostate lineage markers such as prostein (P501S), prostate-specific membrane antigen (PSMA), NKX3.1, and androgen receptor could be of added utility (Figs. 3A–D).55–57 Of these markers, PSMA has lower specificity, and androgen receptor can also be positive in urothelial carcinoma. P501s has the benefit of distinctive clumpy granular immunoreactivity, and NKX3.1 is a very sensitive and specific nuclear antibody.

Figure 3
Figure 3
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Combining some of the above markers with urothelial lineage markers will further facilitate resolving a urothelial versus prostatic carcinoma differential diagnosis. Studies have documented HMWCK positivity in >90% of urothelial carcinomas.56,58 HMWCK is only rarely and focally expressed in prostate carcinoma (8%).56 A cautionary note is warranted given that HMWCK labels squamous epithelia including areas of squamous differentiation in posttherapy recurrent prostate carcinoma lesions. HMWCK positivity that is restricted to areas of squamous differentiation does not exclude the diagnosis of PCa.59 P63 has a greater specificity albeit lower sensitivity for urothelial carcinoma compared with HMWCK (100% specificity and 83% sensitivity).56

Uroplakins are urothelium-specific transmembrane proteins expressed by the majority of noninvasive and up to two thirds of advanced invasive and metastatic urothelial carcinomas as assessed by UPIII.60–64 Although highly specific for urothelial differentiation, UPIII is only of moderate degree of sensitivity (as low as 40%) in high-grade urothelial carcinoma.65 Thrombomodulin is an endothelial cell–associated cofactor for thrombin-mediated activator of protein C. Its expression, predominantly as membranous staining, has been found in 69% to 100% of urothelial carcinomas.56,63,66 Thrombomodulin is only rarely positive in PCa.56,66 It is also expressed by nonurothelial tumors such as vascular tumors, mesotheliomas, and squamous cell carcinomas.66 Compared with UPIII, thrombomodulin has a higher degree of sensitivity but lower specificity as a marker for urothelial carcinoma. In a recent study, p63 was superior to thrombomodulin as a urothelial marker in high-grade tumors.56

GATA3 (GATA binding protein 3 to DNA sequence [A/T]GATA[A/G]) is a member of a zinc finger transcription factor family. Several recent studies have confirmed its utility as a marker for urothelial carcinoma.67–71 In the 2 largest studies by Liu et al69 and Miettinen et al,70 86% and >90% of urothelial carcinomas were positive for GATA3, respectively. The nuclear staining is usually diffuse in >50% of cells. In rare cases, PCas can be focally positive for GATA3.69–71 Finally, CK7 and CK20 are of limited utility in this differential given that they may both be positive in a subset of PCa.72,73

The various prostate and urothelial markers along with their advantages and disadvantages are listed in Tables 2 and 3.

Table 2
Table 2
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Table 3
Table 3
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ISUP Recommendations

Option to use PSA as a first test to identify PCa and GATA3 to identify UC.

If GATA3 is not available, then HMWCK and p63 can be used.

If the tumor is PSA positive with intense staining and HMWCK and p63 negative, the findings are diagnostic of PCa.

If the tumor is equivocal/weak/negative for PSA and negative/focal for p63 and HMWCK, then staining for P501S, NKX3.1, and GATA3 must be performed. Some experts also include PAP in this second round of staining.

If the tumor is negative for PSA and diffusely strongly positive for p63 and HMWCK, the findings are diagnostic of UC.

If the tumor is negative for PSA and moderately to strongly positive for GATA3, it is diagnostic of UC.

Laboratories should be encouraged to use GATA3 for UC and add P501S and NKX3.1 as prostate markers in addition to PSA, p63, and HMWCK.

If GATA3, p501S, and NKX3.1 are not available in equivocal cases, they should be sent out for consultation to laboratories with these antibodies.

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HIGH-GRADE PCA VERSUS BLADDER ADENOCARCINOMA

In the differential diagnosis of bladder adenocarcinoma, one must first consider the possibility of secondary adenocarcinoma involving the bladder either by metastasis or direct invasion, such as from the prostate. Morphologically, there are differences in that bladder adenocarcinoma shares all of the various histologic patterns of adenocarcinoma arising in the gastrointestinal tract. However, if necessary, certain IHC stains can be utilized in the differential diagnosis with PCa. Monoclonal PSA antibodies do not label bladder adenocarcinoma, although polyclonal PSA and PSAP are positive in a significant percentage of bladder adenocarcinomas.74,75 Of the more recently discovered prostatic markers, PSMA lacks specificity but NKX3.1 and P501S do not react with bladder adenocarcinomas.56,76 The advantages and disadvantages of these and other antibodies are listed in Table 4.

Table 4
Table 4
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ISUP Recommendations

PSA (monoclonal antibody), PAP (monoclonal antibody), P501S, NKX3.1, villin, thrombomodulin, CDX2, monoclonal CEA.

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PROSTATIC SMALL CELL CARCINOMA VERSUS HIGH-GRADE PCA

The diagnosis of small cell carcinoma of the prostate is reached on the basis of morphologic features similar to those found in small cell carcinomas of the lung as defined in the 1999 World Health Organization classification criteria of pulmonary neoplasms. Morphologic variations of small cell carcinoma include the intermediate cell type with slightly more open chromatin and visible small nucleoli, which can be difficult to distinguish from high-grade PCa. Further complicating the issue is that in approximately 50% of the cases, the tumors are mixed small cell carcinoma and PCa. In some cases the transition between the small cell and acinar components is abrupt, and in other cases the 2 components merge together. It is critical to identify a small cell component, as prostatic small cell carcinomas are treated with the same chemotherapy as is used in pulmonary small cell carcinomas, whereas advanced high-grade PCa is initially treated with hormonal therapy. Often IHC is utilized in equivocal cases. The advantages and disadvantages of the various antibodies used in this differential diagnosis are shown in Table 5.

Table 5
Table 5
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Using IHC techniques, the small cell component is positive for 1 or more neuroendocrine (NE) markers (synaptophysin, chromogranin, CD56) in almost 90% of cases (Figs. 3E, F).84,85 PSA and other prostatic markers such as P501s are positive in about 17% to 25% of cases, although often very focally (Table 2).84,85 In 24% and 35% of cases, positivity is noted for p63 and HMWCK, markers typically negative in prostatic carcinoma.85 Studies have demonstrated TTF-1 expression in >50% of small cell carcinomas of the prostate, limiting its utility in distinguishing primary small cell carcinoma of the prostate from a metastasis from the lung.84–87

Given the high rate of occult metastases, clinically localized small cell prostate cancer is typically treated aggressively, often with multimodality therapy with chemotherapy and radiation similar to limited-stage small cell lung cancer. Metastatic small cell carcinoma of the prostate is treated with platinum-based combination chemotherapy with regimens similar to those used to treat small cell lung carcinoma.88–91 Some experts treat pure small cell carcinoma with chemotherapy alone, whereas others add androgen deprivation therapy, in cases in which could be important to exclude metastasis or local extension from other sites such as bladder. A technique that can distinguish small cell carcinoma of the prostate from other small cell carcinomas is documentation by fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction of a gene fusion between members of the ETS family of genes, in particular ERG (ETS-related gene) and TMPRSS2, found in approximately one half of the usual PCas.92 In a similar percentage of cases, small cell carcinoma of the prostate is positive for TMPRSS2-ERG gene fusion by FISH.93–98 Importantly, it should be noted that compared with usual acinar carcinoma harboring TMPRSS2-ERG rearrangements, small cell carcinoma with TMPRSS2-ERG rearrangement is not reliably positive for ERG protein by IHC, presumably because of lack of androgen receptor expression in small cell carcinoma.93 In addition, in the setting of standard treatment for castrate-resistant prostate cancer, ERG protein expression may not be present by IHC, requiring the use of FISH. According to one study, there is strong and diffuse membrane staining for CD44 in all prostatic NE small cell carcinomas, whereas in usual PCas, only rare positive scattered tumor cells are CD44 positive.99 However, current work by one of the authors has not substantiated this finding and has concluded that this antibody is not useful in the distinction of high-grade PCa from small cell carcinoma.

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ISUP Recommendations

The diagnosis can be made on the H&E-stained sections in the absence of special stains.

In cases in which the routinely stained sections are equivocal, a combination of prostate markers, NE markers, TTF-1, and ki67 can be used. CD44 has in 1 study claimed to be positive in prostatic small cell carcinoma and negative in usual PCa. However, the results need to be verified.

It should be recognized that not all small cell carcinomas express NE markers. CD56 is the most sensitive, yet least specific. Synaptophysin has the best combination of sensitivity and specificity. Chromogranin is the most specific but is often negative or only shows rare positive cells.

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METASTATIC CARCINOMA UNKNOWN PRIMARY: RULE OUT PCA

Given that there is a treatment for metastatic PCa that can provide symptomatic relief and in some cases increased survival, it is critical to determine whether a metastatic carcinoma is of prostatic origin. There are several antibodies that can be used for this purpose, listed in Table 6. See references for High-grade Prostatic Adenocarcinoma versus Bladder Adenocarcinoma and Poorly Differentiated Prostate Adenocarcinoma versus Urothelial Carcinoma in addition to the ones listed in this chapter.18,40,100–107 One must also be aware that immunoreactivity for PSA and PSAP decreases after androgen deprivation therapy.108

Table 6
Table 6
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ISUP Recommendations

PSA, PAP, prostein, NKX3.1.

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NONSPECIFIC GRANULOMATOUS PROSTATITIS/XANTHOMA VERSUS HIGH-GRADE PCA

One of the principal entities that can be confused with high-grade prostate cancer is nonspecific granulomatous prostatitis (NSGP). Although most cases of NSGP seen on needle biopsy do not histologically resemble prostate cancer, 4% of cases can closely resemble cancer. These cases of NSGP consist of sheets of epithelioid histiocytes, some with prominent nucleoli with abundant granular cytoplasm.109 Xanthomas of the prostate can similarly mimic high-grade PCa.110 If there are difficulties in distinguishing NSGP from poorly differentiated adenocarcinoma, IHC can be utilized (Table 7).

Table 7
Table 7
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ISUP Recommendations

Keratins (AE1/AE3, CAM5.2), CD68.

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ADULT PROSTATE SARCOMA (STROMAL SARCOMA/LEIOMYOSARCOMA) VERSUS SARCOMATOID PCA

The differential diagnosis of a malignant spindle cell tumor in the prostate is sarcomatoid PCa (carcinosarcoma) versus a sarcoma. The most common sarcomas in the prostate in an adult are stromal sarcoma and leiomyosarcoma. Morphologically, leiomyosarcoma has a distinctive fascicular growth pattern that can be distinguished from a sarcomatoid carcinoma. A pitfall is the expression of keratin in some prostate leiomyosarcomas with conflicting studies on the presence of p63 in these tumors. More problematic is the distinction between a stromal sarcoma of the prostate and sarcomatoid PCa (Table 8).111–118

Table 8
Table 8
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ISUP Recommendations

Desmin, PanCK, HMWCK, p63, CD34 (if stromal sarcoma in the differential).

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COLORECTAL ADENOCARCINOMA VERSUS HIGH-GRADE PCA

Colorectal adenocarcinomas may also directly invade the prostate. Usually colorectal adenocarcinomas that invade the prostate are not occult, although occasionally they may present in the prostate. Adenocarcinoma of the rectum infiltrating the prostate may resemble one of the patterns of prostatic duct adenocarcinomas. Histologic features favoring colorectal adenocarcinoma are prominent desmoplasia, “dirty necrosis,” chronic inflammatory response, tall columnar epithelium with mucin, or mucin-positive signet ring cells. If there is difficulty in distinguishing colorectal adenocarcinoma from PCa, IHC is useful (Figs. 4A, B and Table 9).77,119–125

Figure 4
Figure 4
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Table 9
Table 9
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ISUP Recommendations

Prostate markers, CDX2, villin, β-catenin.

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PROGNOSTIC IHC MARKERS

There have been multiple IHC markers that have been proposed for prognostic purposes. The more promising ones that have been studied to a greater extent are listed in Table 10.126–140 A limitation of all of them is that they have not been validated in prospective studies.

Table 10
Table 10
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ISUP Recommendations

Currently, there are no prognostic IHC or molecular studies that are recommended to be routinely performed on biopsy or resection specimens.

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Keywords:

ISUP recommendations; immunohistochemistry; best practices; prostate; atypical small acinar proliferation; small cell carcinoma; metastatic carcinoma; prostatic sarcoma; racemase; p63

© 2014 by Lippincott Williams & Wilkins.

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