Since both resection specimens and needle biopsy samples from the prostate are common in surgical pathology practice, some knowledge of anatomy and the zonal architecture of the normal prostate can be helpful to orient samples as viewed under the microscope and avoid a few specific diagnostic pitfalls. This chapter will include some discussion of the most relevant aspects of anatomy and prostate zones with implications for diagnostic practice; however, for more detailed discussion, other thorough reviews are available.1 The modern understanding of prostatic zonal anatomy was heavily influenced by the pioneering work from McNeal et al.,2,3,4,5 which established the main prostatic zones.

Most core needle biopsies collected via transrectal ultrasound-guided approach are intentionally targeted toward the posterolateral aspects of the gland (particularly the peripheral zone), attempting to have the highest diagnostic yield for cancer while minimizing sampling of benign nodular hyperplasia. However, with the evolution of multiple novel biopsy techniques more recently, other approaches are sometimes taken, including magnetic resonance imaging (MRI)-targeted biopsies of specific lesions, as well as transperineal saturation biopsies that attempt to “map” the prostate for location and extent of any potential cancers.6,7 The histology of these biopsies is generally similar, with the possible exceptions that transperineal biopsies can contain fragments of skin in place of colorectal tissue, and that some may be predominantly fibromuscular stroma, if not targeted at the peripheral zone.

Awareness of these anatomic zones can assist with orienting the prostatic tissue on the slide. In general, whole-mount processing of radical prostatectomy specimens makes orientation easy8; however, since this technique can be challenging for routine adoption in pathology practices, its use is in the minority, with only 16% of participants in an International Society of Urological Pathology (ISUP) consensus using the whole-mount technique.8 Therefore, in conventional sections, several subtle clues may be helpful to distinguish different anatomic regions of the prostate if sections are not clearly labeled or if there is a concern they have been mislabeled.

Figure 1.7. The bladder neck can be discerned microscopically based on larger discrete muscle bundles, in contrast to the confluent smooth muscle of the prostatic stroma.

Figure 1.8. Invasion of the bladder neck muscle by prostatic adenocarcinoma constitutes pT3a.

Figure 1.9. The normal central zone of the prostate has a cribriform-like morphology that may be confused for prostatic intraepithelial neoplasia (PIN) or cancer.

Figure 1.10. The central zone contains frequent “Roman arch” bridging structures.

Figure 1.11. Despite that the central zone morphology (bottom) can be confused for prostatic intraepithelial neoplasia (PIN), it is possible for the central zone to be involved by PIN (top).


Although it is common in clinical language to refer to the prostate “capsule,” the prostate does not have a true capsule anatomically speaking.11 Generally, in the posterolateral regions of the prostate (the areas where assessment for extraprostatic extension is usually most critical), the plane of adipose tissue is typically regarded as the most definitive boundary for organ-confined vs non-organ-confined cancer.9 Another problem with the term “capsule” is that this can also be used by urologists to refer to the plane between the transition zone and the peripheral zone, in which dissections for nodular hyperplasia are carried out. As such, terms such as capsular invasion or penetration should largely be avoided, instead terminologies such as extraprostatic extension or organ-confined could be used.


The prostatic glandular epithelium itself is composed of two cell populations: the secretory and basal cells. The prototypical benign secretory cell layer has pale cytoplasm, an undulating contour, and ovoid nuclei without prominent nucleoli12 (Figure 1.12). Common normal variations within the benign glandular epithelium can include lipofuscin pigment, which can have various colorations in stained tissue sections (brown, golden, but also gray or blue; Figures 1.13,1.14,1.15).13,14 The basal cell layer, when well visualized, and depending on the laboratory preparation, is typically composed of cells with ovoid nuclei, often appearing perpendicular to those of the secretory layer with little to no cytoplasm.15 The basal cells often have a blue-gray or slate staining color (Figures 1.16,1.17,1.18), compared to the darker purple or violet staining of the secretory cell nuclei.16 An unusual finding that can be encountered occasionally in benign (as well as malignant) tissue is so-called Paneth-like neuroendocrine cells. These are scattered interspersed cells within the prostatic glandular epithelium that have brightly eosinophilic granules (Figure 1.19).17,18 Despite being termed “Paneth-like,” this terminology is probably a misnomer, as these are more akin to the gastrointestinal neuroendocrine cells rather than true Paneth cells, with positive immunohistochemical staining for neuroendocrine markers (Figure 1.20).17 This is currently not considered to have any clinical significance, as scattered neuroendocrine cells can be present in both normal prostate tissue and conventional adenocarcinomas.17

Figure 1.12. The normal prostatic glandular epithelium contains secretory cells with pale cytoplasm and oval, purple-staining nuclei.

Figure 1.13. Pigment in benign prostatic glandular epithelium can vary in color. This example is brown.

Figure 1.14. This focus of benign prostatic glands appears dark at low magnification due to cytoplasmic pigment.

Figure 1.15. At high magnification, the same focus from Figure 1.14 shows a dark blue or purple pigment.

Figure 1.16. In well-visualized benign glands, the basal cell layer will contain nuclei with a blue-gray color, distinct from the purple color of the secretory cell nuclei.

Figure 1.17. The basal layer may also have small nucleoli.

Figure 1.18. In some benign glands, prominent nucleoli in the basal cell layer may lead to confusion with prostatic intraepithelial neoplasia (PIN) or cancer.

Figure 1.19. So-called Paneth-like neuroendocrine cells (arrow) can be found in benign prostatic tissue. These are occasional cells with eosinophilic cytoplasmic granules, usually at the base of the glandular epithelium.


Simple atrophy is so common in prostatic tissue that it may debatably be considered a relatively normal finding. In general, it is postulated to be aging-related and potentially a sequela of an inflammatory insult; however, it is possible to encounter atrophy in prostatic specimens even from men at age 30 to 40 years.11,19 Simple atrophy is composed of glands with scant cytoplasm, typically arranged into angulated structures with pointed corners (Figure 1.24), which usually makes it unlikely to mimic malignancy. In contrast to prostate cancer, which often elicits no stromal changes, atrophic glands can be variably rimmed by stromal fibrosis (Figures 1.25 and 1.26).19 Other, more deceptive patterns of atrophy, such as partial atrophy, are discussed later in the sections discussing small gland lesions.


Prostatic nodular hyperplasia is composed of variable proportions of glands and stroma, arranged into circumscribed nodules. This is usually easier to appreciate in larger surgical pathology specimens, such as transurethral resections or radical or simple prostatectomy specimens. In needle biopsy samples, it is for the most part not possible to recognize glandular hyperplasia, since the glandular component of nodular hyperplasia is essentially identical to normal glandular tissue, other than its arrangement into nodules. Therefore,
diagnosis of glandular hyperplasia in needle biopsy samples should typically be avoided20; however, stromal-predominant hyperplastic nodules can sometimes be recognized in needle biopsy samples by a few morphologic clues.

Figure 1.20. Paneth-like cells in the prostate are likely misnamed, as they are more analogous to the basally located neuroendocrine cells (arrow) that have granules beneath the nucleus in this image of the small intestine, in contrast to true Paneth cells (circle), which have larger granules above the nucleus.

Figure 1.21. Some prostate cancers can contain compressed nuclei at the base of the glands, resembling basal cells (arrows).

Figure 1.22. The same case from Figure 1.21 evaluated with double immunohistochemical staining for alpha-methylacyl-CoA racemase (AMACR) and p63 shows positivity for AMACR but no basal cells.

Figure 1.23. Basal cell hyperplasia can narrow the lumen of involved glands. With prominent nucleoli, this may be confused for carcinoma.

It is generally optional to comment on the presence of stromal nodules in needle biopsy samples; however, with the increasing usage of specialized biopsy techniques, such as MRI-targeted biopsy,6,7 it may sometimes be relevant to mention the presence of stromal nodules, when they might account for the clinical “lesion” in a negative biopsy.

Figure 1.24. Simple atrophy is composed of glands with scant cytoplasm, often arranged into jagged glandular shapes with some pointed tips.

Figure 1.25. In contrast to prostate cancer, atrophy often is surrounded by stromal fibrosis or inflammation.

Figure 1.26. This needle biopsy example shows prominent hyalinization around atrophic glands.

Figure 1.27. Occasionally stromal nodules can be detected in prostate needle biopsies. This example shows hypercellular stroma with only a few glands.

Figure 1.28. At higher magnification, the same case from Figure 1.27 shows rare glands and hypercellular stroma with scattered lymphocytes.

Figure 1.29. This example of a prostatic stromal nodule shows eosinophilic fibromuscular stroma with scattered blood vessels showing slightly hyalinized walls.

Figure 1.30. Rarely, prostatic stromal nodules can have such prominent vasculature that they resemble a vascular lesion.

Figure 1.31. At high magnification, prostatic stromal nodules often have occasional scattered lymphocytes.


Encountering seminal vesicle or ejaculatory duct in needle biopsy can occasionally be a source of diagnostic confusion, due to the inherent cytologic atypia and sometimes crowded glandular architecture of these structures.21

An interesting feature of benign seminal vesicle and ejaculatory duct tissue is that amyloid deposition is sometimes present in the stroma surrounding the epithelium, which is thought to be aging-related (Figures 1.39,1.40,1.41,1.42). This amyloid appears to have no relation to systemic amyloidosis and is thought to be composed of semenogelin I.22 Given the lack of apparent clinical significance of this phenomenon, it is debatable whether it should be documented in surgical pathology reports. On the one hand, it is typically clinically insignificant; however, it is possible that it can be noted clinically, such as on imaging studies, mimicking invasion by cancer23,24,25 (see Sample Note).

Figure 1.32. Seminal vesicle tissue can be deceptive in needle biopsy samples. This example demonstrates a few crowded glands at the edge of the core.

Figure 1.33. At higher magnification, the same case from Figure 1.32 shows more variation in nuclear size than typically expected of prostate cancer.

Figure 1.34. Seminal vesicle tissue often has granules of yellow-brown pigment, facilitating recognition.

Figure 1.35. Another clue to the recognition of seminal vesicle tissue is the presence of intranuclear cytoplasmic invaginations or pseudoinclusions, which are rare in prostate cancer.

Conversely, the presence of amyloid in other locations, such as throughout the prostate stroma, or especially in a perivascular location in small prostatic or soft tissue blood vessels, should likely trigger a clinical evaluation for the possibility of systemic amyloidosis (Figures 1.43 and 1.44). Immunohistochemistry can be used to attempt to subtype the amyloid, as antibodies are available to kappa and lambda light chains (AL type) or amyloid A (AA type), among others; however, such evaluation is not always conclusive. When tissue material is limited, a practical approach is to refer paraffin-embedded tissue samples to a laboratory that offers mass spectroscopy for amyloid subtyping, if clinically indicated.

Figure 1.36. Seminal vesicle tissue in needle biopsy samples is often at the end or edge of the core, since the biopsy likely punches into the large lumen.

Figure 1.37. This focus of seminal vesicle glands could be confused for prostatic adenocarcinoma due to crowded round glands.

Figure 1.38. The same case from Figure 1.37 contains some prominent nucleoli. However, clues to the recognition of seminal vesicle tissue include scattered yellow-brown pigment and varied nuclear size.

Figure 1.39. Amyloid deposition is occasionally present in the seminal vesicle or ejaculatory duct, which is thought to have no clinical significance.

Figure 1.40. Amyloid rims benign seminal vesicle glands, which contain some yellow-brown pigment.

Figure 1.41. Congo red staining highlights seminal vesicle amyloid, similar to other forms of amyloid.

Figure 1.42. With polarization, this seminal vesicle with amyloid shows the classic green birefringence.

Figure 1.43. In contrast to seminal vesicle amyloid, which is likely not clinically significant, amyloid in prostatic blood vessels may be a sign of systemic deposition. This case shows large thickened blood vessels at right with benign prostatic tissue at left.

Figure 1.44. At high magnification, the same case from Figure 1.43 shows a waxy, cracked consistency of the vascular amyloid.

Figure 1.45. Ganglia can be found in the periprostatic tissue and occasionally in close juxtaposition to benign prostatic glands.


Ganglia are encountered relatively commonly in prostate specimens and usually pose little diagnostic confusion due to their apparent composition by nerve fibers and large ganglion cells (Figure 1.45). However, paraganglia are rarer and may be a source of diagnostic difficulty due to their similarity to poorly formed gland or solid adenocarcinoma (Figures 1.46 and 1.47).26,27,28,29 Contrasting to prostate cancer, paraganglia are positive for neuroendocrine markers, such as chromogranin, whereas they are negative for prostate-specific markers, such as prostate-specific antigen (PSA).26,27,28,29 Of note, it has been recently recognized that paragangliomas and pheochromocytomas are often positive for GATA3, which may complicate distinction from urothelial carcinoma.30,31 To our knowledge, this has not been studied in normal paraganglia; however, it may be reasonable to suspect that positive staining can also be found in this context.


Immunohistochemistry plays an important role in diagnosis of prostatic specimens, particularly biopsies; however, use of immunohistochemistry should be judicious.
Routine immunohistochemistry in all benign biopsies, or in biopsies with unequivocal cancer, is not appropriate.32 It is typically helpful to use more than one antibody in a multiplex assay or “cocktail” that contains alpha-methylacyl-CoA racemase (AMACR) and one or more basal cell markers. However, there are several possible formulations for this (Table 1.1).

Figure 1.46. Paraganglia in and around the prostate can be more deceptive, as the mononuclear cell pattern can be confused for carcinoma or extraprostatic extension of carcinoma, as the small nests of cells in this case intermingle with adipose tissue.

Figure 1.47. This example of periprostatic paraganglion could be confused for pattern 4 or 5 prostatic adenocarcinoma due to formation of solid nests of cells with pale to clear cytoplasm.

Some noteworthy exceptions to the usual staining patterns of prostate cancer do exist. For example, although prostate cancer inherently lacks basal cells, rare cases of prostatic adenocarcinoma with aberrant p63 positivity in the cancer cells have been described.33,34,35,36,37,38 In contrast to the basal cell distribution shown by p63 staining in lesions with true basal cells, this staining result is typically nonbasal (Figures 1.48 and 1.49) and labels much or all the cancer cells themselves. Prostate cancers with aberrant p63 staining are often atrophic in appearance. Similarly, a minority of prostate cancers can have aberrant positivity for high-molecular-weight cytokeratin in the cancer glands. These are often higher-grade cancers (Figure 1.50).39,40,41,42 Fortunately, these are also typically not the same tumors that have aberrant p63 staining, so that if the two markers are used complementarily, the true absence of basal cells should be detected.

Scenarios Potentially Warranting Immunohistochemical Staining

Of course, the decision to utilize immunohistochemistry in prostate biopsy samples requires the clinical judgment of the reporting pathologist and may be influenced by specific criteria at a given institution regarding surveillance or treatment eligibility. However, some more common scenarios in which there is a stronger or lesser need for immunohistochemistry are shown in Table 1.2 (Figures 1.51 and 1.52).


The most common nonprostatic tissue found in prostate specimens is colorectal tissue captured via the transrectal nature of ultrasound-guided biopsies (Figure 1.53). In most cases, this is readily recognizable as rectal tissue and it poses no diagnostic challenge. However, in exceptional cases, there may be either (1) abnormal findings, such as polyps or inflammatory processes,43 or (2) rectal tissue closely juxtaposed to prostate tissue, mimicking atypical glands or cancer.44 This latter situation can be compounded by the lack of basal cells in colorectal tissue if immunohistochemistry is used, as well as occasional positivity for AMACR in rectal glands.

TABLE 1.1: Immunohistochemical Antibody Combinations for Confirmation of Prostate Cancer





Alpha-methylacyl-CoA racemase (AMACR) + p63

Single color (cytoplasmic vs nuclear)

Technically simpler than dual-color assays, conserves tissue compared with individual antibodies on separate slides

Strong AMACR may mimic or obscure basal cells, lacks additional basal cell detection of high-molecular-weight cytokeratin

AMACR + p63 + high-molecular-weight cytokeratin (cytokeratin 5/6, 14, 34βE12, others)

Dual color

Basal cells appear in a different color than AMACR, conserves tissue compared with individual antibodies on separate slides

Technically more difficult to perform than single-color methods

p63 alone

Single color

More difficult to assess without a concurrent positive marker

High-molecular-weight cytokeratin alone

Single color

More difficult to assess without a concurrent positive marker


Single color or in combination with others

Positive strongly favors adenocarcinoma or occasionally prostatic intraepithelial neoplasia (PIN)

Only positive in approximately 40% of prostate cancer


Single color or in combination with others

Abnormal negative (“loss”) favors malignancy and higher-grade/aggressive cancer

Interpretation of absence of staining can be challenging

Adapted from Epstein JI, Egevad L, Humphrey PA, Montironi R. Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014;38(8):e6-e19.

Figure 1.48. Rare prostate cancers can be p63-positive. This example shows a proliferation of small glands with prominent nucleoli. (Courtesy Ankur R. Sangoi, MD, El Camino Hospital.)

Figure 1.49. The same prostatic adenocarcinoma from Figure 1.48 shows nuclear staining of the cancer glands for p63. Although the adjacent basal cells show both cytoplasmic (high-molecular-weight cytokeratin) and nuclear (p63) staining in a basal distribution, the cancer glands show only nuclear staining for p63, supporting their distinction from a true benign basal cell population. (Courtesy Ankur R. Sangoi, MD, El Camino Hospital.)

Figure 1.50. Rare prostate cancers can be positive for high-molecular-weight cytokeratin, especially high-grade cancers. This example shows intraductal carcinoma with high-molecular-weight cytokeratin staining of the basal cells; however, there is also substantial staining of the cancer cells as well.

TABLE 1.2: Scenarios for Immunohistochemistry Use in Prostate Biopsy




Atypical glands in a single core biopsy


Diagnosis may range from benign (if the presence of basal cells would allow confident classification as a benign mimic such as partial atrophy, Figures 1.51 and 1.52) to atypical or malignant

Atypical glands in additional biopsies with one or more showing Gleason score 3 + 3 = 6 (Grade Group 1) cancer


Some active surveillance criteria use the number of positive biopsies (two or three sites) and percentage (50%) involvement of biopsies to determine eligibility, although this is changing and often depends on the institution and practitioner

Atypical glands in additional biopsies with one or more showing Gleason score 3 + 4 = 7 (Grade Group 2) cancer


In general, prostate cancer management is driven by the high-est-grade biopsy, so the need for confirming additional foci of Gleason score 3 + 3 = 6 (Grade Group 1) in a case with overall Gleason score 3 + 4 = 7 (Grade Group 2) may depend on the institutional criteria for treatment. In most cases, there would not be a significant management difference with additional small foci of Gleason score 3 + 3 = 6 (Grade Group 1) cancer

Atypical glands in additional biopsies with one or more showing Gleason score Gleason score 4 + 3 = 7 (Grade Group 3) or higher cancer


With high-grade cancer, additional small foci of Gleason score 3 + 3 = 6 (Grade Group 1) or Gleason score 3 + 4 = 7 (Grade Group 2) are unlikely to change the clinical management plan

Large cribriform cancer that may be entirely intraductal carcinoma


If there is a possibility that a large cribriform proliferation is entirely intraductal carcinoma, it is often reasonable to confirm with immunohistochemistry. Although some would consider pure intraductal carcinoma to be indication for treatment alone, cases with minimal or no invasion may not be as aggressive as those with associated high-grade invasive cancer. This is an emerging area of interest

High-grade invasive cancer + possible intraductal carcinoma


Although intraductal carcinoma is generally excluded from grading, in the setting of high-grade (pattern 4 or higher) invasive cancer, it is not clear at present that subtracting an intraductal component from the grade improves prognostication

Routine immunohistochemistry of all biopsies


Routine immunohistochemistry of all biopsies prior to morphologic review or for all benign biopsies is not warranted. This has the potential to cause more confusion than clarity, as some benign lesions may have a patchy basal cell layer, in which occasionally glands show none in the plane of section

Figure 1.51. When a small focus of atypical glands is present in a prostate needle biopsy with no definite cancer in other specimens, it is usually worthwhile to perform immunohistochemistry. This case shows a focus of a few crowded round glands adjacent to a benign gland.

Figure 1.52. Using a single-color p63 and alpha-methylacyl-CoA racemase (AMACR) immunohistochemical stain, the same case from Figure 1.51 shows an intact, patchy basal cell layer with moderate staining for AMACR, supporting a benign diagnosis. Despite the AMACR staining, the focus does not show features of prostatic intraepithelial neoplasia (PIN) morphologically.

Figure 1.53. Colorectal tissue is a common contaminant in prostatic needle biopsies. When the fragment is detached and contains apparent blue mucin, lamina propria, and goblet cells, it is usually straightforward to disregard as colorectal tissue.

Figure 1.54. Scenarios in which colorectal tissue can cause challenges in prostatic biopsy specimens include implantation of the colorectal glands into the prostatic tissue. This example shows a single colorectal gland in the middle of the biopsy core, which could be confused for prostatic adenocarcinoma or prostatic intraepithelial neoplasia (PIN) with cytoplasmic vacuoles.

Abnormalities in the squamous tissue from the anal or perineal areas that may be captured in transrectal or transperineal biopsies have been less frequently reported but can be potentially encountered as well. In general, the presence of detached fragments of atypical or malignant cells that are not part of the tissue core should raise consideration of a specimen contaminant before being diagnosed as prostatic malignancy. Some laboratories offer molecular techniques of tissue identity testing to confirm whether a component of the tissue belongs to the same patient or represents a specimen contaminant.

Figure 1.55. This example of colorectal tissue in a prostate biopsy shows a detached colorectal gland (top) in addition to one implanted in the biopsy core (bottom right).

Figure 1.56. This example of colorectal tissue was misdiagnosed in a prostate biopsy as atypical glands suspicious for cancer. The morphology is somewhat distorted, but there is a suggestion of lamina propria.

Figure 1.57. Absence of staining for basal cell markers in this fragment of colorectal tissue may have compounded the confusion with prostatic adenocarcinoma. This example also has no significant alpha-methylacyl-CoA racemase (AMACR) staining in the cocktail stain; however, this does not necessary help resolve the diagnosis, as some prostate cancers are negative and some colorectal tissue can be positive.

Figure 1.58. Although colorectal glands in prostate biopsy may appear hyperchromatic, detached configuration and the presence of lamina propria are helpful to discriminate from prostatic adenocarcinoma.


The most common diagnostic challenge in prostate cancer pathology is a lesion with a histologic appearance of small, round glandular structures, since the most common pattern of low-grade prostate cancer is that of small, ring-shaped glands with a monolayered appearance. This section in the pattern-based approach discusses small gland lesions, including low-grade cancer and its mimics.


Adenosis (Atypical Adenomatous Hyperplasia)

Adenosis or atypical adenomatous hyperplasia are synonymous names that can be used interchangeably.21 Some authors have argued that the designation adenosis has less potential for confusion, since it does not contain the word “atypical,” which may be confused with a suspicious diagnosis (atypical glands or atypical small acinar proliferation)45; however, both names are sufficiently well established in the scientific literature to be used.

Figure 1.59. Adenosis or atypical adenomatous hyperplasia usually manifests as a well-circumscribed nodule, resembling nodular hyperplasia.

Figure 1.60. In adenosis, there is a transition from large benign-appearing glands to small, crowded round glands.

Figure 1.61. At high magnification, the small round glands of adenosis/atypical adenomatous hyperplasia (adenosis) are morphologically similar to typical benign glands.

Figure 1.62. This example of adenosis/atypical adenomatous hyperplasia is particularly deceptive, due to numerous small crowded glands at the edge of the lesion. Crystalloids are present in some of the lumens, further resembling cancer.

Figure 1.63. In this dual-color alpha-methylacyl-CoA racemase (AMACR) and basal cell immunohistochemical stain, the same case from Figure 1.62 shows several of the small glands to lack basal cells and the entire lesion is positive for AMACR. However, several of the small glands have a patchy basal cell layer, arguing against diagnosis of carcinoma.

Figure 1.64. In this example of adenosis, p63 staining shows decreased density of the basal layer in the small glands; however, several basal cells are present and there is not a striking cytologic difference between the glands with basal cells and those without.

Since adenosis has some features that overlap with those of prostatic adenocarcinoma, such as the proliferation of small glands, presence of crystalloids, and a partial lack of basal cells, it has been postulated that it might be a precursor lesion,48 particularly for transition zone cancers. Using molecular techniques, a few studies have found that these lesions are typically lacking the ERG gene rearrangements that are present in approximately 40% of prostate cancers.49,50 However, since ERG rearrangements appear to be less common in transition zone cancers,51,52,53,54 it is unclear if this would be the optimal evidence for refuting the status of adenosis as a precursor. Nonetheless, there is currently no evidence that adenosis carries an increased risk for development of cancer, and thus, no clinical action is currently recommended.21,46 It is also debatable whether it is necessary to document the presence of adenosis in reports. For smaller lesions that are easily recognized as part of a hyperplastic nodule in transurethral resection specimens, it is likely reasonable that they not be specifically mentioned; however, for lesions encountered in needle biopsy or more florid examples in transurethral resection, it is reasonable to document that the focus was evaluated and judged to be adenosis/atypical adenomatous hyperplasia and not cancer.

Sclerosing Adenosis

Sclerosing adenosis is similar in many ways to adenosis/atypical adenomatous hyperplasia. For example, it shares the composition by large, branched (classically benign) glands and smaller, crowded glands. It may also have a discontinuous basal layer, with some of the small crowded glands appearing to lack basal cells.21,46,47 However, the main differences between sclerosing adenosis and usual adenosis are that sclerosing adenosis also contains hypercellular stroma, which may compress some glands into small clusters of cells that could mimic even higher-grade cancer (Figures 1.66,1.67,1.68,1.69,1.70,1.71).55,56,57,58 In normal benign prostate tissue, the basal cells are not myoepithelial (differing from the breast). However, sclerosing adenosis is unique in the prostate, in that the basal cells do have a myoepithelial phenotype, including positive staining for immunohistochemical markers such as S100 or muscle-specific actin (Figures 1.68 and 1.71),55,56,57,58 in addition to the usual p63 or high-molecular-weight cytokeratin positivity of basal cells. Rarely sclerosing adenosis can have a greater degree of nuclear atypia, increasing the mimicry of prostatic adenocarcinoma; however, these cases have been found to still contain a myoepithelial cell layer and have no clear evidence of more aggressive behavior, favoring their similarity to conventional sclerosing adenosis.55

Figure 1.65. Using high-molecular-weight cytokeratin staining in the same lesion from 1-64, similarly several of the small glands appear to lack basal cells, but they are morphologically similar to other small glands with basal cells.

Figure 1.66. Sclerosing adenosis is composed of small benign glands in a cellular stroma that may mimic cancer, including pattern 4 or higher cancer. This example shows a transition from benign glands at upper left to cellular stroma at lower right.

Figure 1.67. At higher magnification, the same case as Figure 1.66 shows numerous compressed glands that may be difficult to distinguish from blood vessels or stromal cells. However, some small clusters of epithelial cells may raise a differential diagnosis of poorly formed glands of prostatic adenocarcinoma.

Figure 1.68. The same case from Figures 1.66 and 1.67 shows numerous glandular structures with basal cells on this single-color p63 and alpha-methylacyl-CoA racemase (AMACR) stain, even more numerous than appreciable by morphology.

Figure 1.69. In other examples of sclerosing adenosis, glands may be more obvious but crowded, leading to concern of fused or poorly formed glands of prostatic adenocarcinoma.

Figure 1.70. This example of sclerosing adenosis shows very cellular stroma with glands that are difficult to recognize.

Figure 1.71. Immunohistochemistry shows a smooth muscle actin-positive cell layer around the glands in this example of sclerosing adenosis, supporting myoepithelial differentiation and contrasting to usual basal cells, which are not myoepithelial.

Figure 1.72. Diffuse adenosis of the peripheral zone is a rare proliferation of benign-appearing but crowded glands, often occurring in younger patients. This specimen from a 45-year-old man shows areas of lobular crowded glands (left) and other areas with less obvious lobular configuration (right).

Diffuse Adenosis of Peripheral Zone

Diffuse adenosis of the peripheral zone is a rare lesion that has been described in only one study to date.59 In contrast to conventional adenosis, which forms a circumscribed nodule in the transition zone, rare examples under this name have been noted to exhibit crowded, nonlobular, but benign-appearing acini in the peripheral zone (Figures 1.72 and 1.73), often in younger patients (average age 49 years).59 These were noted to typically contain an intact, although often patchy, layer of basal cells in the 55% of cases that were evaluated with immunohistochemistry.59 Despite the apparent benign nature of diffuse adenosis itself, the authors noted an association with cancer, suggesting that it be considered a potential risk factor for prostatic adenocarcinoma.59


As noted previously in the Section The Unremarkable and Nonneoplastic Prostate, atrophy is potentially so common in prostate pathology to be considered a relatively normal finding. In particular, simple atrophy (discussed previously) rarely causes diagnostic difficulty. However, several other patterns of atrophy have been described, including simple atrophy with cysts, sclerotic atrophy, postatrophic hyperplasia (also known as hyperplastic
or lobular atrophy), and partial atrophy.19,60 Postatrophic hyperplasia refers to essentially a lobular configuration of atrophic but crowded glands, which are often hyperchromatic (Figures 1.74 and 1.75). This name implies a putative mechanism of proliferation of the atrophic glands; however, whether it instead represents a crowded lobule that has subsequently undergone atrophy remains open to debate. Most of the discussion here will focus on partial atrophy, which has the most potential to mimic prostatic adenocarcinoma.

Partial Atrophy

Partial atrophy is so named because the cells have decreased cytoplasm compared to normal glands, although cytoplasm is not as attenuated as in other types of atrophy. This means that the glandular structures are not necessarily basophilic, leading to potential confusion with prostatic adenocarcinoma.19 In addition, the cytoplasmic height is typically not much greater than the height of the nucleus (Figure 1.76), whereas there may be an abundant amount of lateral cytoplasm before the next nucleus is encountered in a histologic section (Figures 1.77,1.78,1.79,1.80,1.81,1.82,1.83). Nucleoli can also be identifiable, and luminal border is often at least partially straight,

leading to the mimicry of prostatic adenocarcinoma encountered for this entity.61,62,63 Basal cells are often not apparent using morphology alone; however, immunohistochemistry usually reveals a patchy but intact basal cell layer. Nonetheless, some cases may show no definite basal cells by immunohistochemistry, which should not necessarily preclude confident interpretation as partial atrophy in the appropriate context. Although AMACR may be occasionally positive in partial atrophy,61 it is often of limited or weak intensity.62

Figure 1.73. In diffuse adenosis of the peripheral zone, small round glands are morphologically benign but crowded, often with a less lobular configuration.

Figure 1.74. Postatrophic hyperplasia is typically composed of a lobular configuration of glands with an atrophic appearance. Although the glands may appear morphologically crowded and small, the lobular orientation is a clue to the benign diagnosis.

Figure 1.75. At high magnification, this example of postatrophic hyperplasia may mimic cancer due to the small clusters of glands with a hyperchromatic appearance; however, a normal basal cell layer is present.

Figure 1.76. In partial atrophy, glands are small and crowded. Some nuclei are very small and compressed, as if they have been “pinched” (red arrow). The cytoplasm is not much taller than the nuclei (black arrow), and there is abundant lateral cytoplasm before the next nucleus.

Figure 1.77. This example of partial atrophy is composed of larger, dilated glands. Although basal cells are not morphologically obvious, the cytoplasm is not much taller than the nuclei in several areas and the nuclei are not atypical.

Figure 1.78. Occasional prostate cancers can have atrophy-like features. This example shows glands with short and wide cytoplasm resembling partial atrophy; however, areas with prominent nucleoli similar to usual cancer are also present (arrow).

Figure 1.79. In this example of partial atrophy, there is one gland with attenuated cytoplasm and two round glands with a sharp luminal border.

Figure 1.80. Using immunohistochemistry with a dual-color basal cell and alpha-methylacyl-CoA racemase (AMACR) cocktail, the same focus from Figure 1.79 shows extremely rare basal cells and no significant staining for AMACR. Despite the paucity of basal cells, the lesion can be interpreted as benign.

Figure 1.81. This focus of partial atrophy closely mimics cancer, composed of three small round glands.

Figure 1.82. On a single-color p63 and alpha-methylacyl-CoA racemase (AMACR) stain, no basal cells are visualized in the same focus from Figure 1.81. There is no significant AMACR staining.

Figure 1.83. In a high-molecular-weight cytokeratin stain from the same focus as Figures 1.81 and 1.82, rare basal cells are present, supporting interpretation as partial atrophy.

Figure 1.84. Basal cell hyperplasia can manifest as small round glands. This example is relatively evident as having two cell populations.

Basal Cell Hyperplasia (Small Gland Pattern)

Basal cell hyperplasia can exhibit several different histologic patterns, which are discussed in each of the pattern-based sections. Occasionally, basal cell hyperplasia can form small, round glands (Figures 1.84 and 1.85), which may be confused with the usual pattern of prostatic acinar adenocarcinoma. In most cases, this proliferation makes up the majority of, or the entirety of, a hyperplastic nodule, and therefore, the nature of the lesion can be recognized based on its circumscription within a nodule. However, rare cases of basal cell hyperplasia can form only part of a hyperplastic nodule, yielding a pseudoinfiltrative appearance (Figures 1.86,1.87,1.88,1.89,1.90).64 Both normal and hyperplastic basal cells can contain appreciable nucleoli, which can add to the diagnostic difficulty (Figure 1.88). Additionally, basal cell hyperplasia can contain mitotic figures and crystalloids.64

Figure 1.85. This example of basal cell hyperplasia mimicked a low-grade prostatic adenocarcinoma due to extremely crowded arrangement of round glands.

Figure 1.86. Occasionally, basal cell hyperplasia can have a pseudoinfiltrative appearance due to the glands making up only a part of a hyperplastic nodule, raising the possibility that they are cancer glands infiltrating between benign glands.

Figure 1.87. This example of basal cell hyperplasia was extremely deceptive due to its partial composition of a hyperplastic nodule. Some of the basal cell hyperplasia glands contain blue mucin (red arrow), and they appear to infiltrate between benign glands.

Figure 1.88. High magnification of the same case from Figure 1.87 shows prominent nucleoli and blue mucin. See also Figures 1.89 and 1.90.

It is relevant to keep in mind that rare prostate cancers can be p63-positive33,34,35,37 and others, especially high-grade cancers, can be high-molecular-weight cytokeratin positive.39,40,41,42,66 However, fortunately, positivity for both markers typically does not occur in the same case and the staining distribution of staining in such cases is not basally located, instead typically labeling the cancer diffusely in a nonbasal distribution.

Figure 1.89. Immunohistochemistry with a single-color p63 and alpha-methylacyl-CoA racemase (AMACR) stain shows a robust layer of basal cells in all of the pseudoinfiltrative glands from Figures 1.87 and 1.88.

Figure 1.90. The same case from Figures 1.87,1.88,1.89 shows a robust basal cell layer with high-molecular-weight cytokeratin staining.

Figure 1.91. When considering a differential diagnosis between basal cell hyperplasia and prostatic adenocarcinoma, it is helpful to compare the suspicious glands (circle) to the basal cells of obviously benign glands (red arrows).

Figure 1.92. When using immunohistochemistry in basal cell hyperplasia, although the glands appear to be filled with basal cells morphologically, the staining may be more peripheral, as in this example of p63 staining, or in a checkerboard pattern with some morphologically similar cells being negative.

Figure 1.93. The same case of basal cell hyperplasia from Figure 1.92 shows high-molecular-weight cytokeratin only partially in most of the glands, despite their morphologic appearance of being filled by basal cells.

Figure 1.94. The verumontanum sometimes contains a crowded architecture of small round glands, although usually with a normal lobular architecture.

Figure 1.95. At high magnification, the verumontanum glands have benign cytology and often dark-colored luminal concretions.

Figure 1.96. In some examples of verumontanum mucosal glands (or hyperplasia), the dark concretions may be extremely numerous, which can be used as a diagnostic clue if found in a biopsy specimen.

Verumontanum Mucosal Glands, Normal and Hyperplastic

The verumontanum or seminal colliculus is a landmark within the prostatic urethra near the insertion of the ejaculatory ducts that typically forms a rounded or triangular hump in tissue sections, pointed toward the anterior aspect of the prostate gland.1,11,67,68 This can contain small, rounded, crowded glands, which may appear on first examination to be suspicious for adenocarcinoma (Figures 1.94 and 1.95).67 In radical prostatectomy specimens, this is typically not a diagnostic problem, as the restriction of this proliferation to the specific anatomic region of the verumontanum is apparent. However, when especially florid or encountered in a biopsy specimen, this pattern may be deceptive.68 These glands often have concretions similar to corpora amylacea that are more numerous than conventional benign tissue, and frequently, these have a red-orange, bronze, or deep purple color (Figures 1.96,1.97,1.98), different from the typical pink appearance of corpora amylacea.68 Despite the crowded acinar appearance of this lesion, basal cells are appreciable by morphology or immunohistochemistry, and cytologic features are typically bland, contrasting to true adenocarcinomas, which may sometimes extend to the urethra.67,68

Nephrogenic Adenoma

Nephrogenic adenoma is a relatively well-known entity with a proliferation of cells with a renal tubular phenotype, particularly in the urinary bladder; however, it also may cause a diagnostic challenge in the prostatic urethra. Patterns of nephrogenic adenoma include tubular, papillary, and flat.16,46,47,69,70,71 Primarily the tubular pattern is discussed here for its potential to be confused with prostate cancer (Figures 1.99,1.100,1.101,1.102).71 Nephrogenic adenoma was originally considered a metaplastic process, considering its frequent association with inflammation or irritation of the urinary tract, which suggests that it may be a
metaplastic response to injury. However, an interesting study found that in renal transplant recipients, the lesion has the sex chromosomes of the kidney donor rather than the recipient, suggesting that it likely represents implantation and growth of shed renal tubular cells into a site of urinary mucosal injury.72 As such, it seems that nephrogenic adenomas are most consistently positive for renal tubular marker PAX8 (Figure 1.103),73,74 whereas they can have a few different phenotypes resembling perhaps different sites of renal tubular cells, with variable positivity for other markers such as AMACR and GATA3 (Figure 1.104).75

Figure 1.97. In this example, verumontanum glands were captured in a needle biopsy appearing as a complex glandular proliferation but with prominent dark concretions.

Figure 1.98. In this case, verumontanum glands appear distorted in a transurethral resection specimen; however, the dark concretions are a clue that may help to avoid concern for cancer.

Figure 1.99. Nephrogenic adenoma involving the prostatic urethra usually manifests as crowded glands or tubular structures just under the urethral mucosa.

Figure 1.100. In this case of nephrogenic adenoma found in transurethral resection, several tubular structures are present just below the urethral mucosa.

Figure 1.101. The classic pattern of nephrogenic adenoma forms small tubules or glands, which could be confused for prostate cancer.

Figure 1.102. This example of nephrogenic adenoma encountered in a needle biopsy shows an extremely crowded proliferation of tubular structures at the tip of the core, which likely represents the urethral lumen.

Mesonephric Remnant and Hyperplasia

Mesonephric remnants are rare benign inclusions sometimes found in the prostatic or periprostatic tissue, analogous to the counterpart in the gynecologic tract.21,76,77,78 Locations noted have included bladder neck smooth muscle, soft tissue around the seminal vesicle at the prostatic base, within anterior fibromuscular stroma of the prostate, and within the prostatic tissue among acini.76 This lesion may be underrecognized, as some cases likely overlap substantially with lobules of atrophic prostatic glands; however, the more florid and hyperplastic cases may have the potential for diagnostic confusion, being mistaken for prostatic adenocarcinoma or extraprostatic extension of cancer (when in the periprostatic tissue).76 Several features of mesonephric remnant resemble those of nephrogenic adenoma, including positivity for PAX8 immunohistochemistry, as well as formation of small glandular structures with cuboidal cell lining. In contrast to nephrogenic adenoma, which by its nature occurs near urothelial mucosa (eg, the prostatic urethra), mesonephric remnants tend to be found in locations distant from the urethral mucosa. Other features of
mesonephric remnant include a lobular architecture, colloid-like luminal material (Figure 1.107), dilated tubules or cysts, and micropapillary tufts.76 When mesonephric remnants are found within benign prostatic tissue, it is of no clinical significance if they are disregarded as atrophic glands; however, when potentially confused for prostate cancer or extraprostatic extension of cancer, their negative staining for prostatic markers (PSA and others) and positive staining for PAX8 (Figure 1.108) are diagnostically useful.76,78

Figure 1.103. Consistent positive immunohistochemistry for PAX8 is helpful in confirming nephrogenic adenoma, which is rarely, if ever, positive in prostatic adenocarcinoma.

Figure 1.104. If a prostate immunohistochemical “cocktail” is used, such as this p63 and alpha-methylacyl-CoA racemase (AMACR) single-color assay, it may led to confusion with prostatic adenocarcinoma, as nephrogenic adenoma will have no basal cell layer and often cytoplasmic positivity for AMACR.

Figure 1.105. Other features of nephrogenic adenoma include a frequent background of chronic inflammation and a prominent basement membrane layer around the glands (red arrows).

Figure 1.106. This example of nephrogenic adenoma of the prostatic urethra has prominent nucleoli, which could lead to confusion with prostatic adenocarcinoma. The location just under the mucosa of the urethra is a clue.

Benign Glands With Radiation Atypia

A general rule for histopathology of prostate specimens is that marked nuclear pleomorphism tends to argue against prostatic adenocarcinoma and favor another diagnosis, whether it be benign seminal vesicle or ejaculatory duct tissue, benign glands with radiation change, or urothelial carcinoma. As such, apparently random variation in nuclear size within prostatic glandular tissue should often raise suspicion for previous radiation change. Additionally, a patient history of radiation is often not conveyed upon submission of specimens for examination, frequently requiring the pathologist to verify such a
history within available medical records. In benign tissue with radiation change, glands often appear atrophic with scant cytoplasm of the luminal or secretory cells. However, the basal cells are enlarged and sometimes quite atypical and hyperchromatic with prominent nucleoli (Figures 1.109 and 1.110).79,80 Despite this potentially worrisome appearance, lobular architecture can often still be recognized. Radiation change of soft tissues, such as marked vascular damage (Figure 1.111), obliteration of small blood vessels, or atypical cells within nerves can also be a clue to the posttreatment nature of a specimen when not communicated. A recently reported interesting finding that could cause diagnostic confusion is that these basal cells may also be positive for GATA3 immunohistochemistry (Figures 1.112,1.113,1.114),81,82 which could lead to confusion with urothelial carcinoma. Despite the recognition of this phenomenon in prostates with radiation treatment, GATA3 positivity can also be found in benign prostate tissue without a radiation history, although perhaps at a lesser level.81,83 Prostate cancer, in contrast, is consistently negative for GATA3 with extremely rare reported exceptions.81,83,84,85,86,87 If prostatic adenocarcinoma is a diagnostic concern, immunohistochemistry in these glands will show the atypical cells to be positive for basal cell markers.

Figure 1.107. Mesonephric remnants are rare lesions in and around the prostate. This example would likely be disregarded as a benign process such as atrophy; however, when found in periprostatic tissue, this entity may lead to uncertainty. This example is composed of small tubules with eosinophilic colloid-like material.

Figure 1.108. PAX8 positivity can help confirm the diagnosis of mesonephric remnant, which also highlights a lobular architecture in this case.

Figure 1.109. Benign prostatic tissue with radiation effect can display marked nuclear atypia in the basal cells, which may be disconcerting. However, pleomorphism is unusual in prostate cancer and should raise consideration of radiation change.

Figure 1.110. This example of benign prostatic tissue with radiation change demonstrates a lesser degree of nuclear atypia, but this may be a clue to the posttreatment nature of the specimen if not communicated.

Figure 1.111. This blood vessel from a postradiation prostate biopsy shows intimal thickening and enlarged nuclei in the wall, which are clues that the prostate has been previously treated with radiation.

Figure 1.112. This example of radiation atypia in benign prostatic glands demonstrates numerous basal cell nuclei with enlarged nuclei of varying size.

Figure 1.113. Immunohistochemistry in the same case from Figure 1.112 shows substantial GATA3 positivity, which has been recently described in postradiation benign glands.

Figure 1.114. Immunohistochemistry for p63 in the case from Figures 1.112 and 1.113 shows most of the cells to be basal cells, arguing against prostate cancer.

Cowper Glands

Benign Cowper glands (bulbourethral glands) are a rare finding in prostatic samples, as these are located beyond the apex of the prostate around the internal base of the penis; however, they can occasionally be captured in biopsies, especially those from the prostatic apex.16,46,47,88 The small, crowded, foamy gland appearance (Figure 1.115) may lead to confusion with prostatic adenocarcinoma, such as foamy gland variant cancer. However, clues to the nonneoplastic nature of these structures include a lobular or circumscribed configuration surrounding a central duct, with a background of skeletal muscle. Occasional associated benign-appearing glands often transition into the mucinous glands (Figure 1.116). If in doubt, immunohistochemistry can aid in the recognition of Cowper glands, as they typically have positive staining for high-molecular-weight cytokeratin in ductal cells and in a basal-like distribution in some of the lobules. Likewise, p63 often shows at least a patchy positive cell layer (Figure 1.117).


Prostatic acinar adenocarcinoma is, of course, the main concern within the spectrum of “small gland” lesions that has led to the recognition of the numerous benign mimics
discussed here. The classic prostatic adenocarcinoma is composed of crowded, small, ring-shaped glandular structures with a monolayered appearance. Nuclei are enlarged and sometimes hyperchromatic, often with at least focally prominent nucleoli (Figure 1.118). Cytoplasm is also dark or amphophilic compared with reference benign epithelium (Figures 1.119 and 1.120).89 However, prostate cancer differs from many other cancers in that the tumor cells are classically monotonous (not pleomorphic), the glandular shapes are round/regular, and the tumor does not usually elicit a stromal/desmoplastic response.

Figure 1.115. Cowper or bulbourethral glands can appear as crowded small round glands with mucinous features in a needle biopsy, especially from the apex of the prostate.

Figure 1.116. Clues to the recognition of Cowper glands in prostate biopsies include the intimate association with skeletal muscle and associated benign ducts (right).

Figure 1.117. This example of Cowper glands on prostate needle biopsy shows no significant alpha-methylacyl-CoA racemase (AMACR) staining and a patchy p63-positive cell layer on a single-color dual stain for both markers.

Figure 1.118. One of the strongest features for histologic diagnosis of prostatic adenocarcinoma is the presence of prominent nucleoli, as shown in this case with relatively pale round glands, some containing prominent nucleoli.

Diagnostic Criteria for Minimal Prostate Cancer

Although large foci of prostatic adenocarcinoma are usually readily recognizable due to their crowded small gland pattern, cytologic atypia, and infiltrative growth pattern, a common challenge in surgical pathology practice is to determine whether a limited focus of atypical glands in a biopsy sample is sufficient to render the diagnosis of malignancy, overwhelmingly in regard to Gleason score 3 + 3 = 6 (Grade Group 1) cancer.89,90 A commonly used system for evaluating such atypical foci is to tally the histologic features in favor of and against cancer to arrive at an overall assessment (listed in Table 1.3 and illustrated in Figures 1.121,1.122,1.123,1.124,1.125,1.126,1.127,1.128,1.129,1.130,1.131,1.132,1.133,1.134,1.135,1.136,1.137,1.138,1.139,1.140,1.141,1.142,1.143,1.144).89 With numerous features in favor of a diagnosis of cancer and few

or none against, diagnosis of prostatic adenocarcinoma can usually be made. With a mixture of features in favor of and against cancer, diagnostic options typically include benign mimics of cancer, if the findings can be confidently classified with the use of immunohistochemistry. Alternatively, a report of atypical glands/atypical small acinar proliferation may be necessary when a satisfactory explanation for the atypical glands cannot be reached with confidence. Similarly, if there are multiple features against a diagnosis of cancer, but a smaller number of suspicious features, diagnostic options would again include benign mimics or an atypical diagnosis.

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May 16, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Prostate
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