—  LONG COURSE #02  —

The Pathology of Prostate Cancer: From Population Studies to the Molecule
Moderators: Dr. John R. Srigley and Dr. Rodolfo Montironi

Section 5 - Diagnosis Of Adenocarcinoma In Needle Biopsies

Jonathan Epstein
Professor of Pathology, Urology and Oncology
The Johns Hopkins Hospital
Baltimore, MD


Recognition of Limited Cancer on Needle Biopsy
One of the more common problems seen with needle biopsy material is the underdiagnosis of carcinoma in cases with a limited amount of tumor. At the edge of a tumor nodule, one commonly finds only scattered glands of adenocarcinoma infiltrating between non-neoplastic glands. It is not uncommon, therefore, for biopsies of adenocarcinoma of the prostate to yield several cores of tissue containing benign glands and stroma with only a few neoplastic glands intercalated amongst benign glands.

In order to optimize the detection of prostate cancer, specimens should not be submitted in only 2 cassettes (left and right). The first problem is that when there are multiple cores in a given jar, the histotechnologist in processing these needle biopsy specimens, cannot guarantee that the cores will all remain in the same plane of section within the paraffin. This results in histological slides where they may be missing gaps of prostate tissue that the pathologist will not see. This can be critical, as the key focus within a prostate needle biopsy showing the only malignancy may be present in one of these gaps of tissue. A second major concern with throwing multiple cores into one jar, is that the urologist loses information as to where these cores are coming from. In 5%-10% of prostate needle biopsies, the pathologist will render an "atypical, suspicious for carcinoma" diagnosis, necessitating a repeat biopsy. We have demonstrated that the cancer is often near or adjacent to these atypical sites. Consequently, if one knows the sextant region where the initial atypical site has come from, one can focus the repeat biopsy by doing more repeat biopsies in this region and in the adjacent regions. It makes no sense to know where the cores are coming from and have the specific information only to lose it by throwing all the cores, for example from the left side, into one jar.

There is another reason why it is important to know the location of each core. Within the central zone toward the base of the prostate around the ejaculatory duct, there is a close mimicker of high-grade prostatic intraepithelial neoplasia (PIN). If pathologists know that the biopsy that they are looking at comes from the base of the prostate, it is easier for the pathologist to recognize this central zone histology as a mimicker of high-grade PIN, rather than over-diagnosing these lesions as high grade PIN. Recognizing mimickers of high-grade PIN can prevent false positive biopsies and obviate the need for unnecessary repeat needle biopsy. The final reason why it is important to separate cores into 6 distinct jars depending on the sextant location is to help the pathologist identify tumor in the radical prostatectomy specimen when the tumor is extremely focal. In approximately 5% of radical prostatectomy specimens, it may be extremely difficult to identify prostate cancer. These cases represent very small tumors that have been incidentally hit by needle biopsy. If the pathologist knows the approximate location (i.e. sextant region) of the cancer on needle biopsy, the pathologist can then focus their hunt in the radical prostatectomy for prostate cancer in these regions by performing cut-downs and flipping paraffin blocks. I am aware of at least one urologist who has been sued when no cancer was found in the radical prostatectomy, despite an accurate diagnosis of minute cancer of the prostate on needle biopsy. Patients are naturally suspicious when they undergo a major surgical operation and no cancer is found. Knowing the site of origin of the cancer on needle biopsy within the prostate can minimize the likelihood that prostates will be signed out showing no evidence of residual carcinoma. Separating cores into 6 separate jars (one jar or block per each sextant site) is the optimal technique.

The importance of recognizing these cases of prostatic adenocarcinoma relates to the high false-negative rate with core biopsy of the prostate. Approximately 19%-25% of sextant core biopsies which are initially negative may show cancer on subsequent biopsy [1, 2]. Furthermore, a limited amount of tumor on needle biopsy does not equate with a limited amount of cancer in the prostate. In a study of non-palpable prostate cancer diagnosed by needle biopsy, we found that in cases where there was <3mm. of well or moderately differentiated cancer on one needle biopsy core, 21% of the radical prostatectomy specimens contained a moderate or advanced amount of tumor [3]. Only a limited amount of tumor on needle biopsy seen in the setting of low serum PSA values may indicate limited tumor in the prostate [3]. The recognition of prostatic cancer in these cases with limited tumor rests on both the architectural abnormalities resulting from the infiltrating neoplastic glands and the cytologic features of the neoplastic epithelium.

It is important when examining needle biopsy specimens to gain an appreciation of what the normal non-neoplastic prostate looks like in that patient. Even with limited needle biopsy material one can see if the patient's non-neoplastic prostate appears normal composed of tall eosinophilic cytoplasm, or is atrophic consisting of small basophilic or less commonly pale glands. In order to identify limited amounts of cancer on needle biopsy material, first there must be an appreciation of the patient's normal non-neoplastic prostate and then look for glands which do not fit in with the normal prostate. By scanning the non-neoplastic prostate one can also gain an appreciation for the amount of stroma that separates the normal glands. The first step in recognizing limited amounts of tumor on needle biopsy material is the identification of an abnormal architectural pattern. Abnormal patterns include: 1) smaller glands than normal; 2) crowded glands; and 3) glands infiltrating between non-neoplastic glands, and more definitively on both sides of benign glands.

After recognizing that there is an abnormal growth pattern on low magnification, one can proceed to higher magnification. If there are some suspicious glands present, verification that these glands are malignant requires evaluation of cytologic detail at higher magnification. It is often very helpful on high magnification to compare the glands that one is considering as diagnosing as carcinoma to the surrounding benign glands. In order to diagnose certain glands as carcinoma there should be some differences between these glands and the surrounding benign glands.

In most needle biopsy specimens with a limited amount of tumor infiltrating amongst normal glands, the tumor is of intermediate grade with atypical nuclear features. One of the most frequently seen features of malignant glands on needle biopsy is their enlarged nuclei as compared to the surrounding benign nuclei. In addition, small nucleoli can often be seen in the carcinoma as compared to the surrounding benign glands which lack nucleoli. The finding of nucleoli may be helpful in diagnosing cancer of the prostate, although not all malignant glands contain nucleoli. One must also take into account the overall setting in which the nucleoli are seen. With intense chronic or acute inflammation, nucleoli may result within benign reactive glands. Consequently, first an abnormal architectural pattern suspicious for carcinoma must be present before assessing cytologic features such as nucleoli. Hyperchromatism is another feature of prostate cancer nuclei. A feature that may be helpful in establishing the diagnosis of carcinoma is the presence of mitoses, since they are rarely seen in hyperplastic glands. Unfortunately, mitotic figures are uncommon in intermediate grade adenocarcinomas of the prostate. In a recent study, only 11% of consult needle biopsies contained mitoses [4].

The majority of attention in assessing diagnostic criteria for prostate cancer has concentrated within the nucleus. We have noted in prior works that in some carcinomas the cytoplasm is more amphophilic than surrounding benign glands and may be helpful in diagnosing limited carcinoma. In a recent study of needle biopsies seen in consultation, in 60% of the evaluable cases this diagnostic criterion was present and helped to establish a diagnosis of carcinoma [4]. Unfortunately, in 32% of the cases as a whole, one could not utilize the criterion. In these cases, the H&E stain was not ideal and benign glands also exhibited amphophilic cytoplasm. Because we find this feature to be helpful in a large number of cases, one should tinker with one's H&E stains to insure that the cytoplasm of benign glands appears lightly eosinophilic or clear. Straight luminal borders in larger glands with abundant cytoplasm also favor the diagnosis of prostate cancer. Comparably sized benign glands with abundant cytoplasm tend to have papillary infolding or luminal ruffling.

After assessing nuclei and the cytoplasm, one should evaluate luminal contents. Two diagnostic criteria are blue tinged mucinous secretions and pink acellular secretions. Whereas corpora amylacea are prominent in benign glands and rarely seen in cancer, pink amorphous acellular secretions are seen in approximately half of cancers and uncommonly seen in benign glands. This criterion must be used in conjunction with other diagnostic features. One can, on occasion, see benign glands with these pink acellular secretions yet lack any other features of malignancy. Blue intraluminal mucinous secretions, although seen less frequently, appear to be more specific. We have only rarely seen blue secretions in benign glands. The prevalence of these blue tinged secretions appears to be in part influenced by the nature of ones hematoxylin and eosin stain. In some institutions referral material this feature appears to be fairly prevalent whereas in other institutions, such as our own, it is rarely seen. One should not, however, perform mucin stains to aid in the diagnosis of prostate cancer. Although initially reports suggested that acid mucin could distinguish malignant from benign glands [5, 6, 7, 8], articles have shown that acid mucin may be present in mimickers of carcinomas such as adenosis as well as in atrophic glands [9].

Prostatic crystalloids are intraluminal dense eosinophilic crystalline-like structures that appear in various geometric shapes. Biopsy and TUR material reveal an incidence of 10-23% and in cystoprostatectomy or autopsy specimens, the incidence of crystalloids in carcinomas reaches 60% [10, 11, 12, 13]. All studies have noted a relative increased incidence of crystalloids within low grade adenocarcinomas. In a study of cancer on needle biopsy, we found a 25% incidence of crystalloids, and also demonstrated an inverse correlation between the presence of crystalloids and Gleason grade [4]. On occasion, we noted crystalloids within entirely benign glands elsewhere in the case. In some instances these benign glands were adjacent to carcinoma yet in other examples they were present in other areas of the prostate. Studies have shown that when crystalloids are seen in benign glands on prostate needle biopsy, patients are not at increased risk for cancer on subsequent biopsy [14, 15].

Perineural invasion, when present, is one of the few only diagnostic criteria that is diagnostic by itself of prostatic adenocarcinoma. In a series of consecutive needle biopsies containing carcinoma, 20% revealed perineural invasion [16]. In order to use perineural invasion as a diagnostic criteria, the glands in question should encircle the nerve. This is to distinguish perineural invasion by carcinoma from perineural invasion that can sometimes be seen with benign glands [17]. Occasionally, benign prostatic glands may be seen adjacent to prostatic nerves, resulting in compression and indentation of the nerves. Benign glands can even partially surround or be within a nerve. In these cases the lack of circumferential growth of the glands around the nerve as well as the benign features of the gland should prevent one from misdiagnosing adenocarcinoma of the prostate.

In addition to perineural invasion, there are two other features pathognomonic for prostate cancer. Occasionally, intraluminal mucinous secretions are so extensive that they become focally organized. This lesion, known as either mucinous fibroplasia or collagenous micronodules, is typified by very delicate lose fibrous tissue with an ingrowth of fibroblasts [18]. Glomerulations consist of glands with a cribriform proliferation that is not transluminal. Rather, these cribriform formations are attached to only one edge of the gland resulting in a structure superficially resembling a glomerulus [18, 19]. In most cases with either perineural invasion, mucinous fibroplasia, or glomerulations, there is overt carcinoma, but in some cases these features are the key to establishing a diagnosis of carcinoma.

Carcinomas Mimicking Benign Glands
Just as there are benign mimickers of prostate cancer, some cancers closely resemble benign prostate glands in their architectural pattern and may not be recognized as malignant.

Pseudohyperplastic prostate cancer is characterized by the presence of larger glands with branching and papillary infolding. [20, 21]. The recognition of cancer with this pattern is based on the architectural pattern of numerous closely packed glands as well as nuclear features more typical of carcinoma. A variant of pseudohyperplastic adenocarcinoma composed of markedly dilated glands with abundant cytoplasm may be particularly difficult to recognize as malignant. This form of cancer can be recognized by the appearance of numerous large glands that are almost back-to-back with straight even luminal borders, and abundant cytoplasm. Comparably sized benign glands either have papillary infoldings or are atrophic. The presence of cytologic atypia in some of these glands further distinguishes them from benign glands. It is almost always helpful to verify pseudohyperplastic cancer with the use of immunohistochemistry for high molecular weight cytokeratin. As with foamy gland cancer, pseudohyperplastic cancer, despite its benign appearance, may be associated with intermediate grade cancer and can exhibit aggressive behavior (ie. Extraprostatic extension).

Foamy gland cancer must be recognized as carcinoma by its abundant foamy cytoplasm, its architectural pattern of crowded and/or infiltrative glands, and frequently present pink acellular secretions [22]. Although the cytoplasm has a xanthomatous appearance, it does not contain lipid, but rather empty vacuoles [23]. More typical features of adenocarcinoma such as nuclear enlargement and prominent nucleoli are frequently absent, which makes this lesion difficult to recognize as carcinoma. Despite its benign cytology, 96% of the cases when there is an associated non-foamy cancer it is Gleason score >4, such that foamy gland carcinoma appears best classified as intermediate grade carcinoma. In foamy gland carcinoma the cytoplasm is copious with nuclei occupying <10% of the cell height. Characteristically, the nuclei in foamy gland carcinoma are small, round, and densely hyperchromatic. The nuclei in foamy gland carcinoma are actually rounder than those of benign prostatic secretory cells.

Atrophic prostate cancers are rare and may be present on needle biopsy, usually unassociated with a prior history of hormonal therapy [24, 25]. The diagnosis of carcinoma in these cases is made on: 1) a truly infiltrative process with individual small atrophic glands situated between larger benign glands; 2) the concomitant presence of ordinary less atrophic carcinoma; and 3) greater cytologic atypia than is seen in benign atrophy.

The importance of not underdiagnosing prostatic adenocarcinoma on needle biopsy relates back to the relatively high false-negative rates with needle biopsy of prostatic carcinoma. In cases where the needle biopsy material is strongly suspicious for carcinoma but the pathologist does not feel comfortable in establishing the diagnosis, what usually transpires is that the needle biopsy is called atypical and a repeat biopsy is recommended. However, because of the high false-negative rates with needle biopsy of prostatic carcinoma, if the repeat biopsy or biopsies do not contain diagnostic material, it does not negate the findings on the initial biopsy and does not exclude the presence of carcinoma within the patient. Therefore, in those cases in which the initial histologic material is strongly suspicious for carcinoma but the pathologist does not feel comfortable in establishing this diagnosis, and subsequent biopsies do not show carcinoma, the material should be sent for consulting opinion rather than assuming that the first biopsy was benign.

Most Common Mimickers of Prostate Cancer on Needle Biopsy
The diagnosis of carcinoma should not be based solely on any one of the features mentioned below but can be more confidently made when several of the features are present. Although the features listed below are more commonly seen in carcinoma, there are exceptions where benign glandular proliferations may also show these features. The most common mimickers of prostate cancer on needle biopsy are atrophy [26], adenosis [27], and nonspecific granulomatous prostatitis [28], and high grade PIN [29].

Atrophy is best diagnosed at medium to low magnification. Although the glands may appear infiltrative, they appear invasive as a patch not as individual glands infiltrating in between and on both sides of larger benign glands. At low power, atrophic glands have a very basophilic appearance. This basophilic appearance is due to their scant cytoplasm and crowded nuclei such that at low magnification one is merely seeing a nuclear outline of the gland. Longitudinal tangential sections of atrophic glands results in cords of cells that can further mimic cancer. In some cases there may be associated fibrosis, which gives the atrophic glands a more infiltrative appearance that has been termed sclerotic atrophy. A characteristic finding in some cases is the presence of a centrally dilated atrophic gland surrounding by fibrosis and clustered smaller glands, which has been termed "post-atrophic hyperplasia (PAH)". Atrophy uniformly labels with high molecular weight keratin in contrast to negative staining in adenocarcinoma. A variant of atrophy that may cause confusion with carcinoma is "partial atrophy". Partial atrophy lacks the basophilic appearance of fully developed atrophy as the nuclei are more spaced apart. The presence of crowded glands with pale cytoplasm may lead to an overdiagnosis of low-grade adenocarcinoma. At higher power, however, the glands have benign features characterized by undulating luminal surfaces with papillary infolding. Most carcinomas have more straight, even luminal borders. In addition, the glands are partially atrophic with nuclei in areas reaching the full height of the cytoplasm. The nuclear features in partial atrophy tend to be relatively benign without prominent nucleoli. One should hesitate diagnosing cancer when the nuclei occupy almost the full cell height and the cytoplasm has the same appearance as surrounding more obvious benign glands.

Adenosis (atypical adenomatous hyperplasia) is one of the closest mimickers of prostate adenocarcinoma on needle biopsy as it is difficult to appreciate its characteristic lobular pattern. Probably the most important differentiating feature of adenosis seen on H&E stain is that within a nodule of adenosis there are elongated glands with papillary infolding and branching lumina typical of more benign glands, yet in their nuclear and cytoplasmic features they look similar to the adjacent small glands suspicious for carcinoma. At higher power, adenosis is typically composed of small glands with pale to clear cytoplasm, as opposed to some carcinomas, which have more amphophilic cytoplasm. Occasional single cells or poorly formed glands are not uncommon in a nodule of adenosis and probably represent tangential sections of small glands. Usually, adenosis has bland appearing nuclei without nucleoli, yet fairly prominent nucleoli may be present, which should not lead to the diagnosis of carcinoma. . Corpora amylacea are commonly seen in adenosis, and are rare in carcinoma. Only 2% of cases of adenosis contain blue intraluminal secretions visible on hematoxylin and eosin-stained sections, a feature common in low-grade carcinomas. Foci of adenosis often contain crystalloids, sometimes in great number. As few as 10% of the glands in a nodule of adenosis may be labeled with antibodies to high molecular keratin, although usually more than half of the glands will show some staining. The stain is also patchy within a given gland, with sometimes only 1 to 2 basal cells identified. If some glands suspicious for adenosis lack high molecular weight cytokeratin immunoreactivity, yet are otherwise indistinguishable from adjacent glands which demonstrate basal cell keratin immunoreactivity, the absence of a basal cell layer in some glands should not be used to diagnose the lesion as carcinoma.

Although most cases of nonspecific granulomatous prostatitis seen on needle biopsy do not histologically resemble prostate cancer, 4% of cases can closely resemble cancer. These cases of non-specific granulomatous prostatitis consists of sheets of epithelioid histiocytes some with prominent nucleoli with abundant granular cytoplasm. The key feature to avoid a misdiagnosis of cancer is to recognize the other inflammatory cells in nonspecific granulomatous prostatitis, such as scattered neutrophils, lymphocytes, plasma cells, and eosinophils. Although it may be difficult to appreciate on needle biopsy specimens, non-specific granulomatous prostatitis initially is localized around ruptured ducts and acini. If there are difficulties in distinguishing non-specific granulomatous prostatitis from poorly differentiated adenocarcinoma, immunohistochemistry can be utilized. These epithelioid cells will be negative for PSA, PSAP, and pancytokeratin, and positive for various histiocytic markers.

The presence of associated clinical findings such as elevated serum PSA levels, abnormal transrectal ultrasound findings, or abnormal rectal exam should not factor heavily into the diagnosis of adenocarcinoma on needle biopsy. All of these tests have relatively low sensitivities and specificities and the diagnosis of carcinoma should be rendered solely on histological grounds. For example in non-specific granulomatous prostatitis the rectal exam can feel nodular like cancer, the serum PSA may be as high as 30 ng/ml, and the ultrasound appearance can be hypoechoic identical to cancer.

Summary to Systematic Approach to Diagnosing Cancer
The approach of diagnosing adenocarcinoma of the prostate consists of making a mental balance sheet, in one column features favoring a diagnosis of carcinoma and the other features favoring a benign diagnosis. At the end of evaluating a case, if all the criteria line up on one side of the balance sheet, even if there are limited number of suspicious glands, then one can reliably establish a diagnosis of carcinoma. In cases where there are several features favoring a diagnosis of carcinoma yet other favoring a benign diagnosis those cases should be signed out as being suspicious but not diagnostic for cancer with recommendation for repeat biopsy.

ARCHITECTURAL FEATURES SUGGESTIVE OF CARCINOMA
  1. Finding of small glands infiltrating in between larger benign glands where otherwise one would expect to see only stroma.

  2. The presence of glands infiltrating haphazardly in different directions within the stroma.

  3. The presence of back-to-back glands which do not merge in with surrounding more recognizably benign glands.

  4. Areas of increased cellularity which are not as densely basophilic as collections of lymphocytes.


CYTOLOGIC FEATURES SUGGESTIVE OF CARCINOMA
  1. Nuclear enlargement with or without nucleoli when compared to surrounding more recognizably benign glands.

  2. Nuclear hyperchromasia.

  3. Adjacent high grade PIN, as long as the small atypical glands are to numerous or far enough away from the PIN so as not to represent outpouchings or tangential sections off of the PIN.

  4. Presence of mitoses.

  5. The presence of individual epithelial cells.

  6. Amphophilic cytoplasm in glands suspicious for carcinoma in contrast to surrounding benign glands which have pale to clear cytoplasm.

  7. Relatively large glands which have a crisp even luminal surface without the ruffling and undulations seen in comparably sized benign glands.


ADJUNCTIVE FINDINGS SEEN WITH CARCINOMA
  1. Presence of intraluminal blue-tinged mucinous secretions seen on H&E sections.

  2. The finding of numerous intraluminal prostatic crystalloids.

  3. The finding of pink amorphous intraluminal secretions.


FEATURES THAT ARE VIRTUALLY PATHOGNOMIC FOR PROSTATE CANCER
  1. Perineural invasion

  2. Mucinous fibroplasia (collagenous micronodules).

  3. Glomeruloid structures.


FEATURES THAT SHOULD MAKE ONE HESITATE IN DIAGNOSING CARCINOMA
  1. Presence of acute and chronic inflammation where nuclei may be enlarged with reactive nucleoli and often have an atrophic cytoplasm.

  2. The presence of a densely cellular lesion suggestive of high-grade prostate carcinoma yet confounded by the presence of acute or chronic inflammation, which may represent non-specific granulomatous prostatitis.

  3. The presence of epithelioid cells suggestive of high-grade prostate cancer centered on ruptured and intact glandular spaces, which may represent non-specific granulomatous prostatitis.

  4. The presence of either fully or partially atrophic glands despite having an infiltrative appearance.

  5. The presence of small glands with minimal atypia merging in with similar glands which appear more recognizably benign, which may represent adenosis.

  6. High grade PIN with only a few adjacent atypical glands, where one cannot rule out tangential sections or outpouchings off of the PIN.


Use of Immunohistochemistry as an Adjunct in the Diagnosis of Limited Adenocarcinoma of the Prostate Cancer
There are cases which some pathologists may not feel comfortable diagnosing as adenocarcinoma based on the architectural pattern of small glands infiltrating in between larger benign glands if there is a lack of cytologic atypia. In these cases where there are a large number of atypical glands present for evaluation, the use of antibodies that label basal cells of the prostate may resolve the diagnosis. The most commonly used antibody used to label basal cells has been high molecular weight cytokeratin [30, 31, 32, 33, 34, 35, 36]. More recently, antibodies to P63, which is a nuclear stain, has also been shown to label basal cells of the prostate [37, 38, 39]. One study that compared high molecular weight cytokeratin and P63 have showed P63 to be slightly superior [39]. In some cases, there will be faint staining of cancer glands with antibodies to high molecular weight cytokeratin; this staining is nonspecific if it is not seen in a basal cell distribution and is still supportive of a malignant diagnosis. More rarely, one can see occasional cancer cells that are strongly positive for antibodies to high molecular weight cytokeratin, yet as long as these cells are not in a basal cell distribution, these cells represent aberrant expression of the antigen in cancer. The use of high molecular weight cytokeratin when presented with only a few atypical glands is not as diagnostic, since benign glands may not show uniform positivity with this marker. Negative staining for high molecular weight cytokeratin is most diagnostic when more than a few glands are present for evaluation and the morphologic features are very suspicious for carcinoma. Rather than used to establish a diagnosis of cancer, we use the high molecular weight cytokeratin stain to help verify a suspicious focus as cancer. If we favor although are not sure that a focus is benign and the stain is negative, we will diagnose it as atypical rather than as cancer.

AMACR, a cytoplasmic protein also known as P504S, has recently been recognized as a tumor marker for several cancers and although its role in prostatic carcinogenesis is unclear, several recent studies have shown that AMACR expression is significantly up-regulated in prostate cancer [40, 41, 42, 43, 44]. By immunohistochemistry, the majority of prostate cancers (80%-100%) are positive for AMACR although a high proportion of high grade prostatic intraepithelial neoplasia (PIN), some foci of adenosis, and also some entirely benign glands have also been reported positive for this marker. As negative staining for basal cell markers especially in a small focus of atypical glands is not necessarily diagnostic of prostate cancer, positive staining for AMACR can increase the level of confidence in establishing a definitive malignant diagnosis. Although ours and previous findings confirm that AMACR is an excellent marker for the detection and diagnosis of prostate adenocarcinoma, caution should be applied in interpreting the immunohistochemical results. Different sensitivity and specificity have been reported among different groups. These are likely the result of the use of different antibodies, different tissue fixation, or other subtle differences in tissue preparation and methods of immunohistochemical staining. Negative AMACR staining in small suspicious glands is not necessarily sufficient for a benign diagnosis. In addition, we have demonstrated that pseudohyperplastic adenocarcinoma and atrophic adenocarcinoma of the prostate, variants of prostate cancer that are particularly difficult to diagnose, are less frequently (62%-77%) positive for AMACR.

In general, the use of immunohistochemistry for prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) is not helpful in distinguishing benign versus malignant glandular lesions of the prostate since both conditions are positive. One of the few instances in which immunohistochemistry for PSAP and PSA is useful is when one sees crushed cellular material suspicious for cancer in and around a nerve or diffusely infiltrating the stroma as individual cells. In these cases the identification of the atypical cells as being of prostatic epithelial origin by their immunoreactivity with PSA or PSAP can establish a diagnosis of carcinoma of the prostate.

References:

General References:

Amin MB, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, et al. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scan J Urol Nephrol (Suppl) (May) 39: 20-33, 2005.

Epstein JI. Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy. Mod Pathol (Mar) 17:307-15, 2004.

Epstein JI: Prostate Biopsy Interpretation. 3rd Edition. Lippincott William and Wilkins, New York (2002).

Eble JN, Sauter G, Epstein JI, Sesterhenn I. WHO Classfication of Tumours: Pathology and Genetics. Tumours of the Urinary and Male Reproductive System IARC Press, Lyon France (2004)

Specific References:

  1. Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol 1994; 151:1571-1574.

  2. Rabbani F, Stoumbakis N, Kava B, Cookson MS, Fair WM. Incidence and clinical significance of false-negative sextant prostate biopsies. J Urol 1998;159;1247-1250.

  3. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of non-palpable (stage T1c) prostate cancer. JAMA 1994;271:368-374.

  4. Epstein JI. Diagnostic criteria of limited adenocarcinoma of the prostate on needle biopsy. Hum Pathol 1995;26:223-229.

  5. Huckill PB, Vidone RA: Histochemistry of mucus and other polysaccharides in tumors: Carcinoma of the prostate. Lab Invest 1967;16:395-406.

  6. Pinder SE, McMahon RFT: Mucins in prostatic carcinoma. Histopathol 1990;16:43-46.

  7. Ro GY, Grignon DJ, Troncoso P, et al: Mucin in prostatic adenocarcinoma. Semin Diagn Pathol 1988;5:273-283.

  8. Taylor NS: Histochemistry in the diagnosis of early prostatic carcinoma. Hum Pathol 1979;10:513-520.

  9. Epstein JI, Fynheer J. Acidic mucin in the prostate: can it differentiate adenosis from adenocarcinoma? Human Pathol 1992;23:1321-1325.

  10. Holmes E. Crystalloids of prostatic carcinoma: Relationship to Bence-Jones crystals. Cancer 1977;39:2073-2080.

  11. Jensen PE, Gardner WA, Piserchia PV. Prostatic crystalloids: Association with adenocarcinoma. Prostate 1980;1:25-30.

  12. Ro JY, Ayala AG, Ordonez NG, Cartwright J, Mackay B. Intraluminal crystalloids in prostatic adenocarcinoma: immunohistochemical,electron microscopic, and x-ray microanalytic studies. Cancer 1986;57:2397-2407.

  13. Ro JY, Grignon DJ, Troncoso P, Ayala AG. Intraluminal crystalloids in whole-organ sections of prostate. The Prostate 1988;13:233-239.

  14. Anton RC, Chakraborty S, Wheeler TM. The significance if intraluminal prostatic crystalloids in benign needle biopsies. Am J Surg Pathol 1998; 22:446-449.

  15. Henneberry JM, Kahane H, Epstein JI. The significance of intraluminal crystalloids in benign prostatic glands on needle biopsy. Am J Surg Pathol 1997; 21:725-728.

  16. Bastacky SI, Walsh PC, Epstein JI. Relationship between perineural tumor invasion on needle biopsy and radical prostatectomy capsular penetration in clinical stage B adenocarcinoma of the prostate. Am J Surg Pathol 1993; 17:336-341.

  17. Ali TZ, Epstein JI. Perineural involvement by benign prostatic glands on needle biopsy. Am J Surg Pathol 29:1159-1163, 2005.

  18. Baisden BL, Kahane H, Epstein JI. Perineural invasion, mucinous ibroplasias and glomerulations: diagnostic features of limited cancer on prostate needle biopsy. Am J Surg Pathol 23:918-924, 1999.

  19. Bostwick DG, Wollan P, Adlakha K. Collagenous micronodules in prostate cancer. Arch Pathol Lab Med. 1995; 119:44-447.

  20. Levi AW, Epstein JI. Pseudohyperplastic prostatic adenocarcinoma on needle biopsy & simple prostatectomy. Am J Surg Pathol 2000;24:1039-1046.

  21. Humphrey PA, Kaleem Z, Swanson PE, et al. Pseudohyperplastic prostatic adenocarcinoma. Am J Surg Pathol 1998;22:1239-46.

  22. Nelson RS, Epstein JI. Prostatic carcinoma with abundant xanthomatous cytoplasm: foamy gland carcinoma. Am J Surg Pathol 1996;20:419-26.

  23. Tran TT, SenGupta E, Yang XJ. Prostatic foamy gland carcinoma with aggressive behavior: Clinicopathologic, immunohistochemical, and ultrastructural analysis. Am J Surg Pathol 2001;25:618-623.

  24. Cina SJ, Epstein JI. Adenocarcinoma of the prostate with atrophic features. Am J Surg Pathol 1997;21:289-295.

  25. Egan AJM, Lopez-Beltran A, Bostwick DG. Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process. Am J Surg Pathol 1997;21:931-35.

  26. Oppenheimer JR, Epstein JI. Partial atrophy in prostate needle cores-another diagnostic pitfall for the surgical pathologist. Am J Surg Pathol 1998;22:440-445.

  27. Gaudin PB, Epstein JI. Adenosis of the Prostate: Histologic features in needle biopsy specimens. Am J Surg Pathol 1995; 19:737-747.

  28. Oppenheimer JR, Kahane H, Epstein JI. Granulomatous prostatitis on needle biopsy -Characterization and clinical correlation of 124 cases. Arch Pathol Lab Med 1997; 121:724-729.

  29. Epstein JI , Grignon DJ, Humphrey PA, McNeal JE, Sesterhenn IA, Troncoso P, Wheeler TM. Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol 1995; 19:873-886.

Immunohistochemical References:

  1. Goldstein NS, Underhill J, Roszka J, et al. Cytokeratin 34 beta E-12 immunoreactivity in benign prostatic acini. Quantitation, pattern assessment, and electron microscopic study. Am J Clin Pathol 1999; 112: 69-74.

  2. 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.

  3. Hedrick L, Epstein JI. Use of keratin 903 as an adjunct in the diagnosis of prostate carcinoma. Am J Surg Pathol 1989;13:389-96.

  4. O'Malley FP, Grignon DJ, Shum DT, Usefulness of immunoperoxidase staining with high-molecular-weight cytokeratin in the differential diagnosis of small-acinar lesions of the prostate gland. Virchows Archiv - A, Pathological Anatomy & Histopathology 1990;417:191-6.

  5. Shah IA, Schlageter MO, Stinnett P, et al. Cytokeratin immunohistochemistry as a diagnostic tool for distinguishing malignant from benign epithelial lesions of the prostate. Mod Pathol 1991;4:220-4.

  6. Brawer MK, Peehl DM, Stamey TA, et al. Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Research 1985;45:3663-7.

  7. Nagle RB, Ahmann FR, McDaniel KM, et al. Cytokeratin Characterization of Human Prostatic Carcinoma and Its Derived Cell Lines. Cancer Research 1987; 47:281-286.

  8. Shah RB, Zhou M, LeBlanc M, Snyder M, Rubin MA.Comparison of the basal cell-specific markers, 34betaE12 and p63, in the diagnosis of prostate cancer. Am J Surg Pathol 2002; 26:1161-8.

  9. Parsons JK, Gage WR, Nelson WG, De Marzo AM. p63 protein expression is rare in prostate adenocarcinoma: implications for cancer diagnosis and carcinogenesis. Urology 2001 58:619-24.

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