The peripheral zone (where most cancers are thought to originate), a crescent-shaped area that rims the lateral and posterior areas of the prostate
The transition zone (the epicenter of benign prostatic hyperplasia), typically manifesting as bilateral periurethral circumscribed nodules, although sometimes asymmetrical
The central zone (relatively infrequently involved by cancer), a cone-shaped area that becomes more prominent toward the base of the prostate, adjacent to the ejaculatory ducts
The anterior fibromuscular stroma, an anterior area that often lacks glandular structures, although not always
Skeletal muscle is admixed with the prostate stroma in the anterior and apex.1,9 If there is a concern that apex and base margins are not correctly labeled, the presence of skeletal muscle usually favors apical location (Figure 1.1)
Since skeletal muscle intermingles with the prostate in the apex and anterior, glands within skeletal muscle are not necessarily malignant (Figure 1.2)
Malignant glands within skeletal muscle do not necessarily constitute extraprostatic extension, but this often indicates close proximity to the prostatic apex (see Sample Note)10 (Figure 1.3)
The verumontanum usually forms a triangular protuberance in the urethra at mid-prostate.1 This “arrow” consistently points toward the anterior (Figure 1.4)
The paired ejaculatory ducts are located posterior to the urethra on each side of midline, usually visualized in sections from mid-gland or the base of the prostate (Figure 1.5). In conventional cassettes, one ejaculatory duct may be present in each (left/right) posterior section. A rich vascular network is often visible in the posterior midline surrounding the ejaculatory ducts (Figure 1.6)
Figure 1.1. Skeletal muscle is admixed with the prostate in the apex (shown here) and anterior, which may assist in orientation of tissue sections.
Figure 1.2. Benign glands can be admixed with skeletal muscle. This is not necessarily an indicator of malignancy.
Figure 1.3. Malignant glands within skeletal muscle do not necessarily constitute extraprostatic extension, but this often indicates proximity to the prostatic apex.
Figure 1.4. The verumontanum is a protuberance in the prostatic urethra that points toward the anterior, which can be helpful for orientation.
Figure 1.5. The ejaculatory ducts are located posterior to the urethra at the base of the prostate, just left and right of midline.
Figure 1.6. There is often a rich vascular network (left) surrounding the ejaculatory ducts (right).
Depending on the extent of dissection, sections from the base of the prostate may contain larger muscle bundles, consistent with bladder muscularis propria, that contrast to the confluent fibromuscular stroma of the prostate (Figure 1.7). Involvement of these larger bundles microscopically constitutes pT3a prostate cancer (bladder neck invasion)9 (Figure 1.8)
The anterior fibromuscular stroma is often devoid of glandular tissue, which can serve to distinguish it from posterior peripheral zone in tissue sections
The central zone is located in the midline of the prostate posteriorly, predominantly toward the base of the prostate, and has unique histologic features, often including dense fibromuscular stroma, slightly larger and more haphazardly arranged nuclei, and “Roman arch” bridging1,11 (Figures 1.9 and 1.10). This can be mistaken for high-grade prostatic intraepithelial neoplasia (PIN), but does not have the hyperchromatic nuclei or prominent nucleoli of true PIN. Nonetheless, it is possible for true PIN to involve the central zone (Figure 1.11)
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 1.9. The normal central zone of the prostate has a cribriform-like morphology that may be confused for prostatic intraepithelial neoplasia (PIN) or cancer.
Figure 1.11. 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).
Prostatic adenocarcinoma, Gleason score 3 + 3 = 6 (Grade Group 1), involving 40% of the length of one core (4 mm tumor focus)
Carcinoma involves skeletal muscle—see Comment
Extraprostatic extension can be identified in needle biopsies when malignant cells are identified in adipose tissue
Carcinoma cells closely approaching adipose tissue on one side only does not necessarily constitute extraprostatic extension
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.
In optimal tissue sections with benign glands, basal cells can be readily distinguished from secretory cell nuclei by their slightly different staining qualities (blue-gray or slate color rather than purple or violet) (Figures 1.16,1.17,1.18)
In lesions suspicious for cancer, compressed nuclei at the base of the glandular epithelium are not necessarily basal cells, especially if they do not have a strikingly different staining quality than the suspicious nuclei (Figures 1.21 and 1.22)
Immunohistochemistry for basal cell markers should always be undertaken for morphologically suspicious lesions, even if they have compressed nuclei at the base of the gland that might be basal cells
Basal cells can have relatively prominent nucleoli, which can mimic cancer, especially with basal cell hyperplasia that narrows the lumen or obscures the secretory cell layer (Figure 1.23). Comparison to basal cells of adjacent obviously benign glands can be helpful, along with immunohistochemistry for basal cell markers
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 1.18. In some benign glands, prominent nucleoli in the basal cell layer may lead to confusion with prostatic intraepithelial neoplasia (PIN) or cancer.
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 1.21. 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.
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 1.27. 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.
Benign seminal vesicle and ejaculatory duct tissue often show a striking degree of nuclear size variation (Figures 1.32 and 1.33), much greater than that of prostate cancer, which is paradoxically monotonous
Large globules of yellow-brown pigment are often present within the cytoplasm of the cells (Figure 1.34)
Nuclei of benign seminal vesicle/ejaculatory duct tissue may contain intranuclear cytoplasmic invaginations (nuclear pseudoinclusions), which is conversely rare in prostate cancer (Figure 1.35)
In biopsy samples, seminal vesicle tissue is often located at the tip or edge of the biopsy core, presumably because the biopsy needle punches into the main lumen and no longer can capture tissue (Figure 1.36)
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.
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 1.41. 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 1.44. At high magnification, the same case from Figure 1.43 shows a waxy, cracked consistency of the vascular amyloid.
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 1.47. 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.
TABLE 1.1: Immunohistochemical Antibody Combinations for Confirmation of Prostate Cancer
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.)
TABLE 1.2: Scenarios for Immunohistochemistry Use in Prostate Biopsy
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 1.55. 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.
Occurs in the transition zone of the prostate as a part of hyperplastic nodules, typically manifesting as a circumscribed hyperplastic nodule (Figure 1.59)
Composed predominantly of usual benign, branched glands
At the outer edge, the glands are small and round, imparting resemblance to low-grade prostatic adenocarcinoma (Figures 1.60 and 1.61)21,46,47
May also have a patchy or discontinuous basal layer using immunohistochemical staining (Figures 1.62,1.63,1.64,1.65) and some degree of AMACR positivity, compounding the mimicry of prostate cancer21,46,47
May have identifiable nucleoli or luminal crystalloids (Figure 1.62), brightly eosinophilic structures typically forming geometric shapes47
However, no significant cytologic difference between the small round glands that lack basal cells (or appear to) and those that do contain basal cells
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 1.65. 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 1.69. 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.
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.
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 1.77. 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 1.84. Basal cell hyperplasia can manifest as small round glands. This example is relatively evident as having two cell populations.
Basal cells inapparent by morphology
Small, crowded, round glands with pale cytoplasm
Often straight luminal border
Some nucleoli visible
Decreased basal apical cell dimension (cytoplasm barely taller than the nucleus)
Large lateral cytoplasm dimension (abundant lateral cytoplasm before the next nucleus)
Occasional small, dark, “pinched” nuclei
Basal cells often present in patchy distribution using immunohistochemistry (may be completely absent in some of the glands)
AMACR often minimal or negative (but sometimes positive)
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.
Similarity of nuclei with nucleoli to the basal cells of adjacent benign glands (Figure 1.91)
Recognition of an apparent dual cell population despite nucleoli or atypia
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 1.93. 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.
Predominantly lobular architecture
Often immediately beneath urothelium
Corpora amylacea/orange-red concretions often numerous
Basal cells identifiable by morphology or immunohistochemistry
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.
Can have a prostate cancer-like staining pattern with typical prostate immunohistochemical cocktails (absence of basal cells and AMACR positivity) (Figure 1.104)
Positivity for high-molecular-weight cytokeratin in the tubules in a nonbasal distribution75 and positivity for PAX8 can be used to confirm the diagnosis
Other morphologic clues include the following:
Prominent basement membrane layer around many of the tubules/glands (Figure 1.105)
Frequent localization near the mucosa of the urethra
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 1.105. Other features of nephrogenic adenoma include a frequent background of chronic inflammation and a prominent basement membrane layer around the glands (red arrows).
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 1.108. 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.
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.
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.