Genitourinary: Prostate, bladder, and kidney pathology

Prostate

1)

Post-atrophic hyperplasia

Differential diagnosis: Atrophic prostatic adenocarcinoma ( Table 5.1 )

Clinical features

Post-atrophic hyperplasia (PAH) of the prostate is a benign lesion that may be encountered incidentally or as potential target of directed biopsies after MRI imaging. Typical mean age of presentation is 50, but can be seen at any age. PAH is typically encountered in the peripheral zone (PZ) compared with the transition zone (TZ) of the prostate.

TABLE 5.1

Post-atrophic Hyperplasia Versus Atrophic Prostatic Adenocarcinoma (PAC)

	Post-Atrophic Hyperplasia ( Fig. 5.1 )	Atrophic PAC ( Fig. 5.2 )
Location	PZ > TZ	PZ > TZ
Histologic features Low power	Lesion appears basophilic at low power due to nuclei occupying full cell height with scant cytoplasm	Less basophilic at low power due to scant yet appreciable cytoplasm
	Preservation of lobular architecture containing central dilated duct with surrounding proliferation of small round acini	Infiltrative or haphazard process between benign acinar structures Sclerotic stromal response typically not present
	Often associated with sclerotic stromal response
High power	Occasional prominent nucleoli and mitotic figures commonly seen in association with inflammatory milieu	Cytologic atypia with nuclear enlargement and prominent nucleoli is required for the diagnosis
		Frequently associated with conventional acinar PAC
Immunohistochemistry stains	Positive for basal cell markers (p63, HMWCK) Negative for AMACR	Negative for basal cell markers (p63, HMWCK) AMACR is variably positive

PZ, Peripheral zone; TZ, transition zone.

Fig. 5.2, In atrophic cancer, glands demonstrate marked reduction in cytoplasm mimicking completely atrophic glands. However, in contrast to complete atrophy, there is still relatively abundant amphophilic cytoplasm. Significant cytologic atypia argues against the diagnosis of benign atrophy. Glands also impart an infiltrative growth. The presence of conventional acinar adenocarcinoma (lower right corner) may be present and provides an additional diagnostic clue.

Pathologic features ( Fig. 5.1 )

Low-power architectural features

This lesion maintains preservation of lobular architecture with a dilated central duct surrounded by proliferation of small round distorted acini. Stroma typically shows sclerosis and chronic inflammation.

Fig. 5.1, At low power, post-atrophic hyperplasia is characterized by a circumscribed/lobulated collection of small dark atrophic acini with round to distorted contours arranged around a larger dilated duct. The dark appearance of the lesion at low power may arouse a suspicion for cancer but is due to scant cytoplasm rather than abundant amphophilic/granular cytoplasm seen in cancer. The stroma surrounding acini is usually sclerotic.

High-power cytologic features

Nuclei occupy full cell height with lack of appreciable cytoplasm. Prominent nucleoli can be common with mitotic figures, which are usually seen in the presence of an inflammatory milieu.

Immunohistochemical features

Basal cell markers are positive. AMACR is typically not expressed.

2)

Partial atrophy

Differential diagnosis: Prostatic adenocarcinoma ( Table 5.2 )

Clinical features

Partial atrophy of the prostate is a benign entity that is one of the most common and troublesome benign mimickers of prostate cancer. Typical mean age of presentation is 50. Partial atrophy is typically encountered in the PZ.

TABLE 5.2

Partial Atrophy Versus Prostatic Adenocarcinoma (PAC)

	Partial Atrophy ( Fig. 5.3 , 5.4 A–C)	PAC
Location	PZ > TZ	PZ > TZ
Histologic features Low power	Crowded small-/medium-caliber glands with reduced cytoplasm, placed laterally to nuclei giving a distinct pale appearance	Crowded small/medium caliber glands exhibiting cytoplasmic amphophilia
	Haphazard or disorganized growth common but lacks infiltrative architecture	Infiltrative between benign acinar structures
	Luminal borders range from undulated to straight with poorly formed glands appearance	Typically “punched out”/straight luminal borders
High power	Slight nuclear enlargement with frequent small nucleoli but lacks prominent nucleoli, mitoses, apoptosis	Nuclear enlargement, prominent nucleoli and hyperchromasia. Mitosis may be occasionally present
	Occasional blue mucin and crystalloids can be present	Luminal secretions, crystalloids, blue mucin common
Immunohistochemistry stains	Frequent patchy positivity for basal cell markers; may entirely lack basal cell staining AMACR expression is frequently seen. Lacks ERG overexpression	Negative for basal cell markers AMACR is expressed in majority of cases ERG overexpression seen in up to 50% of cases

PZ, Peripheral zone; TZ, transition zone.

Pathologic features ( Figs. 5.3 and 5.4 A–C)

Low-power architectural features

This lesion comprises small-/medium-caliber pale glands that often present with disorganized or haphazard growth. Glands have reduced cytoplasm, placed laterally to nuclei giving a distinct pale appearance at low power. The luminal borders of the acini range from star shaped with undulated borders to poorly formed.

Fig. 5.3, Most partial atrophy lesions are composed of a lobular arrangement of crowded glands with lumina ranging from round to stellate/undulating. Note pale, clear cytoplasm placed laterally to the nuclei, lack of nuclear enlargement and macro-nucleoli, as well as the presence of few completely atrophic glands within the focus.

High-power cytologic features

Nuclei may be slightly enlarged with frequent small nucleoli but lack prominent nucleoli, mitoses, and apoptosis. Occasional intraluminal blue mucin can be present.

Immunohistochemical features

Basal cell markers frequently demonstrate patchy positivity with some may entirely lacking basal cell staining. AMACR can be also frequently expressed. Small proportion of lesion may demonstrate immunophenotype of prostatic adenocarcinoma (PAC) characterized by lack of basal cells with AMACR overexpression, an important pitfall to keep in mind ( Fig. 5.4 A–C). ERG overexpression is not seen.

Fig. 5.4, Partial atrophy composed of a crowded proliferation of predominantly small glands with pale cytoplasm similar to the adjacent benign glands. In addition to partially atrophic glands, there are several completely atrophic glands, a very useful diagnostic clue (A) . At high power, small micro-nucleoli are visible (B) . Immunohistochemistry for PIN cocktail antibodies (brown chromogen = p63; red chromogen = AMACR) demonstrate rare basal cells and weak AMACR expression, important pitfalls. Such immunostaining pattern in the context of appropriate morphology is acceptable for the diagnosis of partial atrophy (C) .

3)

Benign prostatic tissue with radiation therapy effect

Differential diagnosis: Prostatic adenocarcinoma with radiation therapy effect ( Table 5.3 )

Clinical features

Benign prostatic tissue with radiation therapy effect (RTE) typically presents in patients treated with radiation therapy. RTE can be seen many years after therapy. Patients frequently present with asymptomatic hematuria due to radiation necrosis. The clinical history of prior radiation therapy, either brachytherapy or external beam radiation, for treatment of PAC is pertinent. Marked epithelial atypia tends to persist for a longer time (up to 6 years), particularly in patients treated with brachytherapy. Can occur equally in the PZ and TZ.

TABLE 5.3

Benign Prostatic Tissue (BPT) With Radiation Therapy (RTE) Effect Versus Prostatic Adenocarcinoma (PAC) With RTE

	BPT With RTE ( Fig. 5.5 )	PAC With RTE ( Fig. 5.6 )
Location	PZ = TZ	PZ > TZ
Histologic features Low power	Maintains lobular architecture	Infiltrating pattern of poorly formed glands or single cell pattern
	Atrophic and reduced glands with increased stroma	Abundant cytoplasmic vacuoles with partially atrophic appearance
High power	Epithelium with random cytologic atypia with some nuclei exhibiting bizarre pleomorphism and smudgy chromatin	Nuclei may appear pyknotic. Atypia typically is uniform with frequent prominent nucleoli
		Gleason score is not provided for PAC exhibiting RTE
Immunohistochemistry stains	Positive for basal cell markers. AMACR is negative	Negative for basal cell makers. AMACR is positive

PZ, Peripheral zone; TZ, transition zone.

Fig. 5.6, In residual adenocarcinoma demonstrating radiation treatment effect, cancer glands grow in a haphazard manner, show frequent tumor breakdown with poorly formed glands and single cells, relatively abundant cytoplasm, and uniform cytologic atypia. Nuclei are small and frequently shrunken.

Pathologic features ( Fig. 5.5 )

Low-power architectural features

This lesion usually maintains the overall lobular architecture of glands. Glands are atrophic and reduced, with an increased stromal component due to RTE.

Fig. 5.5, In post-radiation biopsies, there is an overall paucity of glands. Glands are atrophic and exhibit random cytologic atypia including occasional markedly enlarged nuclei, a tell-tale feature for radiation atypia. However, the cytologic atypia is random and degenerative in nature, and is characterized by hypochromatic nuclei with frequent cytoplasmic vacuolization.

High-power cytologic features

The epithelium of the acini displays marked random nuclear atypia in which some nuclei have bizarre pleomorphism and smudgy chromatin. PAC that is sufficiently well differentiated rarely would produce this degree of atypia. The acini maintain the basal cell layer, which is helpful in distinguishing from malignancy.

Immunohistochemical features

Basal cell markers are positive in prostatic tissue with RTE, and AMACR is not expressed.

4)

Basal cell hyperplasia

Differential diagnosis: High-grade prostatic intraepithelial neoplasia, basal cell carcinoma, p63 positive adenocarcinoma (pac) ( Table 5.4 )

Clinical features

Basal cell hyperplasia is a benign entity that is typically associated with benign prostatic hyperplasia. Typically occurs in the TZ. Can be associated with androgen deprivation therapy (ADT) effect.

TABLE 5.4

Basal Cell Hyperplasia Versus High-grade Prostatic Intraepithelial Neoplasia (HGPIN) Versus Basal Cell Carcinoma Versus p63-Positive Prostatic Adenocarcinoma (PAC)

	Basal Cell Hyperplasia ( Fig. 5.7 A and B)	HGPIN ( Fig. 5.8 )	Basal Cell Carcinoma ( Fig. 5.9 A and B)	p63-Positive PAC ( Fig. 5.10 A–C)
Location	TZ > PZ	PZ > TZ	TZ > PZ	PZ > TZ
Histologic features Low power	Maintains lobular architecture or may show proliferation of isolated large glands	Isolated or crowded glands	Infiltrative process	Infiltrative
	Solid and incomplete nests or large glands with undulating lumina; cellular proliferation is away from luminal aspect; hypercellular stromal cells characteristic of BPH often present	Large glands with tufting, micropapillary or flat architecture	Variably sized nests, cribriforming glands and trabeculae in an infiltrative process. Desmoplastic stroma, perineural invasion, extraprostatic extension, and necrosis are common	Atrophic individual glands with cord-like pattern
High power	Multilayering of basal cells with scant cytoplasm and frequent prominent nucleoli. Nuclei are ovoid, “coffee bean–like” with frequent grooves	Luminal proliferation of columnar secretory cells with relatively abundant cytoplasm. Prominent nucleoli visible at 20×, occasional mitotic activity	Basal cells with multilayering with prominent nucleoli	Nuclei may show stratification, lack pleomorphism; may be admixed with usual PAC
Immunohistochemistry stains	Positive for basal cell markers; negative for AMACR, typically lacks diffuse positivity for BCL2	Frequently patchy positive for basal cell markers; positive for AMACR	Positive for basal cell markers; diffusely positive for BCL2, prostate markers including NKX3.1 are negative	Positive p63 and AMACR, negative for HMWCK, prostate markers including NKX3.1 are positive

BPH, Benign prostatic hyperplasia; PZ, peripheral zone; TZ, transition zone.

Fig. 5.8, At scanning power, high-grade prostatic intraepithelial neoplasia glands are architecturally similar to but appear darker than the adjacent benign glands. At 20× magnification, the secretory cells have crowded and stratified nuclei that are enlarged and have coarse and clumpy chromatin with relatively more cytoplasm between nuclei. Importantly, large and conspicuous nucleoli are present in the secretory cells.

Fig. 5.9, Basal cell carcinoma (BCC) with a solid and cribriform architecture, mimicking basal cell hyperplasia (A) . The distinction from basal cell hyperplasia is especially difficult in needle biopsy samples, as cells can be relatively bland and infiltrative features may not be easily appreciated. In contrast to basal cell hyperplasia, tumor cells in BCC are dense, haphazardly arranged with infiltrative features characterized by edematous desmoplastic stroma, destruction of smooth muscle, and perineural invasion (B) . Infiltrative growth is the hallmark of BCC and is required to differentiate from florid basal cell hyperplasia.

Fig. 5.10, Prostate cancer positive for p63. Atrophic-appearing glands with stratification infiltrate between benign prostate glands (A) . They are lined with several layers of cancer cells with poorly formed lumen. The nucleoli are prominent (B) . All the cancer glands were negative for HMWCK (34βE12, not shown) but were uniformly positive for p63 (C) . Rather than being in basal cell distribution, the staining is found in all the cancer cells. Prostate cancer positive for p63 is exceedingly rare and probably represents a form of prostate cancer with basal cell differentiation.

Pathologic features ( Fig. 5.7 A and B)

Low-power architectural features

This lesion shows a nodular proliferation composed of both completely solid nests admixed with incomplete nests that often exhibit small gland or large gland architecture, including cribriform architecture. Overall, the proliferation consists of multilayered basal cells and lacks an infiltrative pattern.

Fig. 5.7, In basal cell hyperplasia, a range of growth patterns is observed. Isolated large glands with nuclear stratification mimic high-grade prostatic intraepithelial neoplasia. Nuclei are arranged like a pack of cigars without visible cytoplasm and are coffee bean–like with frequent grooves and vesicular glassy chromatin. Prominent nucleoli are frequently seen. Nuclear proliferation is seen away from lumen (A) . In resection specimens, a nodular architecture suggestive of benign prostate enlargement is typically present. Calcifications are common. Note the presence of background cellular spindle cells, suggestive of a benign proliferative process and is a useful diagnostic clue (B) .

High-power cytologic features

The proliferation of basaloid cells typically undermines the secretory cells and can have prominent nucleoli. Nuclei are oriented like a “pack of cigar” with scant cytoplasm. Nuclei are ovoid, coffee bean-like with frequent grooves.

Immunohistochemical features

Basal cell markers are positive. AMACR is typically not expressed.

5)

High-grade prostatic intraepithelial neoplasia

Differential diagnosis: Central zone glands ( Table 5.5 )

Clinical features

High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative neoplastic precursor lesion that is seen in the 50s to elderly men, although it is not rare in 40s. Detected as an incidental finding and by itself, does not elevate serum prostate-specific antigen (PSA). Clinical significance of HGPIN as a marker of unsampled PAC on repeat biopsy has been substantially reduced in the contemporary extended biopsy. However, multiple cores involvement (involving >1 core) and/or multifocal HGPIN and ERG overexpression is still considered important risk factors for unsampled cancer and in this setting a repeat biopsy is recommended.

TABLE 5.5

High-grade Prostatic Intraepithelial Neoplasia (HGPIN) Versus Central Zone (CZ)

	HGPIN	CZ ( Fig. 5.11 A and B)
Location	PZ > TZ	CZ, base of prostate
Histologic features Low power	Medium to large prostatic glands of size of normal glands lined by crowded epithelial cells with cytologic atypia	Medium to large prostate glands of size of normal prostate glands. May have papillary infolding, cribriform formation, and roman bridges
	Increased cytoplasmic amphophilia gives a distinct darker appearance at low power than adjacent benign glands	Lined by tall pseudostratified epithelium with distinct cytoplasmic eosinophilia (a helpful feature)
	Architectural patterns: tufted, micropapillary, flat, and loose cribriform. The diagnosis of cribriform HGPIN is discouraged. Nuclei in roman bridges are round and lack streaming in relation to bridges	Nuclei in roman bridges stream parallel in relation to bridges (a helpful feature)
High power	Hyperchromasia, nuclear overlap, enlarged nuclei, prominent nucleoli that are easily observed at 20× magnification and infrequent mitosis. Cytologic atypia is of secretory cells involving luminal cells	Atypia seen is typically basal cell in nature. Secretory cells lacks prominent nucleoli
Immunohistochemistry stains	A patchy or continuous basal cell layer seen with basal cell markers; variable AMACR expression common; small subset may exhibit ERG overexpression typically in setting of adjacent ERG-positive PAC	Positive basal cell markers; negative for AMACR and ERG

PZ, Peripheral zone; TZ, transition zone.

Fig. 5.11, Central zone histology is typically a mimicker of high-grade prostatic intraepithelial neoplasia (HGPIN); however, prominent cribriform architecture in some cases may mimic cancer. This histology is typically seen in biopsies from the base of the prostate. In the central zone, glands are complex with frequent papillation and undulating architecture with pseudostratified lining epithelium. At low magnification, glands demonstrate distinct cytoplasmic eosinophilia (A) . Roman bridges and cribriform architecture are common. In contrast to HGPIN, nuclei stream parallel to bridges in comparison with perpendicular orientation in HGPIN (B) .

Pathologic features

Low-power architectural features

This lesion consists of medium to large glands of the size of normal prostate acini, lined by crowded epithelial cells that demonstrate cytologic atypia. There are four major architectural patterns: tufted, micropapillary, flat, and rarely loose cribriform. The diagnosis of cribriform HGPIN in biopsy setting is not discouraged and such lesion is often classified as atypical intraductal proliferation (AIP; see Section 10 on page 237 for further discussion). Glands stand out as being darker than normal glands with prominent cytoplasmic amphophilia. May have papillary infolding and roman bridges, but nuclei lack streaming in relation to the bridges to distinguish from normal central zone glands.

High-power cytologic features

The abnormal cytologic features include: hyperchromasia, nuclear overlap, enlarged nuclei, prominent nucleoli that are easily observed at 20× magnification, and rarely mitoses. A basal cell layer is typically preserved but may be indistinct.

Immunohistochemical features

Basal cell markers highlight intact or a discontinuous basal cell layer around the involved ducts or acini. AMACR is expressed in acinar cells variably. ERG overexpression is seen in about 18% of cases that typically have adjacent ERG-positive PAC. ERG overexpression in isolated HGPIN is typically not seen.

6)

Prostate adenosis (adenomatous hyperplasia)

Differential diagnosis: Prostatic adenocarcinoma ( Table 5.6 )

Clinical features

Prostatic adenosis is a benign entity that is more commonly seen in transurethral resection or radical prostatectomy specimens. Typically occurs in the TZ but can be seen in the PZ when diffuse, and referred to as diffuse adenosis of the peripheral zone (DAPZ). DAPZ has an increased risk of PAC on subsequent re-biopsy.

TABLE 5.6

Prostate Adenosis Versus Prostatic Adenocarcinoma (PAC)

	Prostate Adenosis ( Fig. 5.12 A–C)	PAC
Location	TZ > PZ	PZ > TZ
Histologic features Low power	Maintains lobular architecture. DAPZ has diffuse involvement in multiple cores	Infiltrating pattern
	Smaller glands are admixed with larger benign-appearing glands without any cytoplasmic or cytologic differences. Hypercellular stroma, characteristic of benign prostate enlargement is often present and provides a useful clue to the diagnosis.	Small glands infiltrating between benign glands differ in cytoplasmic and cytologic characteristics
	Corpora amylacea and intraluminal crystalloids are common	Corpora amylacea is not seen
	Intraluminal blue mucin may be present	Intraluminal blue mucin common
High power	Pale-clear cytoplasm	Cytoplasm is amphophilic
	Indistinct or small nucleoli	Nuclear enlargement, hyperchromasia, and prominent nucleoli are present
Immunohistochemistry stains	Frequent patchy or fragmented positivity for basal cell markers. Weak to moderate AMACR can be present, ERG is not expressed	Negative for basal cell makers. AMACR is positive, ERG overexpression in up to 50% cases

DAPZ, Diffuse adenosis of the peripheral zone; PZ, peripheral zone; TZ, transition zone.

Pathologic features ( Fig. 5.12 A–C)

Low-power architectural features

This lesion shows a lobular collection of glands. Glands can be crowded and appear back-to-back when diffuse. Smaller glands are admixed with larger benign-appearing glands and are similar in appearance without any cytoplasmic or cytologic differences. Commonly associated with corpora amylacea and rarely, intraluminal blue mucin can be present. DAPZ involves multiple cores. Hypercellular stroma, characteristic of benign prostate enlargement, is often present and provides a useful clue to the diagnosis.

Fig. 5.12, At low power, adenosis is characterized by a circumscribed collection of variably sized glands (A) . Within the nodule, small round acini are admixed with larger benign-appearing glands with papillary infolding. There are no obvious cytoplasmic or cytologic differences between them. Essentially, small and large glands merge with each other imperceptibly. At high power, the columnar cells have abundant pale to clear cytoplasm and bland-appearing nuclei with inconspicuous to small nucleoli (B) . The stroma between the glands is densely cellular, a feature to suggest a benign reactive nature. Basal cell markers typically demonstrate a discontinuous/patchy-staining pattern, with some glands lacking the staining (C) .

High-power cytologic features

The cytoplasm is pale-clear with indistinct or small nucleoli.

Immunohistochemical features

Basal cell markers are frequently patchy positive with some glands retaining basal cells, while some may entirely lack basal cells. As long as glands that have positive basal cells and glands that are negative have a similar appearance, this staining pattern is considered compatible with the diagnosis of adenosis ( Fig. 5.12 C). Weak to moderate AMACR expression is seen in subset of cases. ERG overexpression is not seen.

7)

Sclerosing adenosis

Differential diagnosis: High-grade prostatic adenocarcinoma ( Table 5.7 )

Clinical features

Sclerosing adenosis of the prostate is a benign entity that is more commonly seen in transurethral resection or radical prostatectomy specimens, and rarely on needle core biopsy. Typically occurs in the TZ.

TABLE 5.7

Sclerosis Adenosis Versus High-grade Prostatic Adenocarcinoma (PAC)

	Sclerosing Adenosis ( Fig. 5.13 A and B)	High-grade PAC
Location	TZ > PZ	PZ > TZ
Histologic features Low power	The presence of few well-circumscribed cellular nodules composed of a mixture of well-formed and poorly formed glands, single epithelial cells, and cellular spindled cells, mimicking high-grade PAC is a typical finding	Infiltrating pattern with single cell or poorly formed/fused gland pattern
	Hyaline sheath of collagen can be seen surrounding glands	Lacks collagen sheath
	Dense spindle cell component	Usually lacks stromal response
High power	Glandular component with pale-clear cytoplasm and bland nuclei; blue mucin can be seen	Glandular component with amphophilic cytoplasm and prominent nucleoli
	Single cell component with occasional prominent nucleoli	Single cell component with prominent nucleoli
Immunohistochemistry stains	Positive for basal cell markers, SMA and S100 highlights myoepithelial cells	Negative for basal cell makers, AMACR is positive, SMA is negative

PZ, Peripheral zone; TZ, transition zone.

Pathologic features ( Fig. 5.13 A and B)

Low-power architectural features

This lesion is relatively well circumscribed and is composed of a mixture of well-formed glands, poorly formed or compressed glands, single epithelial cells, and cellular spindled cells. A hyaline sheath of collagen can be seen surrounding glands. A striking feature of this lesion is the dense spindle cell component. The presence of few well-circumscribed cellular nodules in the TZ mimicking high-grade prostate cancer is a typical finding and should prompt a consideration for the diagnosis of sclerosing adenosis.

Fig. 5.13, This transurethral resection of the prostate (TURP) specimen demonstrates a proliferation of poorly formed and complex glands mimicking high-grade prostate carcinoma. Low-power recognition is a key. It typically forms a well-circumscribed nodule of tightly packed glands (A) . At high magnification, glands demonstrate complex proliferation, poorly formed glands with slit-like lumina, fused glands, and even single cells with signet ring cell–like features, mimicking high-grade cancer. Stroma surrounding the glands is cellular and hyalinized (B) . Prominent nucleoli, crystalloids, and blue mucin are common. When one or more well-circumscribed cellular lesions mimicking high-grade prostate cancer are encountered in TURP or biopsies from the transition zone of the prostate, sclerosing adenosis should be ruled out.

High-power cytologic features

The glandular component has pale-clear cytoplasm and bland nuclei. The single cell component may have prominent nucleoli.

Immunohistochemical features

Basal cell markers are positive in the glandular component. Basal cells exhibit myoepithelial differentiation and are positive for smooth muscle actin (SMA) and S100 protein.

8)

Pseudohyperplastic prostatic adenocarcinoma

Differential diagnosis: Crowded benign prostatic glands ( Table 5.8 )

Clinical features

Pseudohyperplastic PAC is a variant morphology of PAC that may be a mimic of crowded benign prostate glands or benign prostate hyperplasia. It typically occurs in the PZ.

TABLE 5.8

Pseudohyperplastic Prostatic Adenocarcinoma (PAC) Versus Crowded Benign Glands

	Pseudohyperplastic PAC ( Fig. 5.14 A–D)	Crowded Benign Glands
Location	PZ > TZ	TZ > PZ
Histologic features Low power	Crowded larger glands with branching and papillary infolding of the lumen that mimic as benign prostate hyperplasia or crowded benign glands. Conventional PAC often is present and provide a useful clue	Crowded glands of variable size with branching and papillary infolding
	Tall columnar cells with abundant mildly amphophilic cytoplasm and basally located nuclei along the basement membrane	Large benign glands with abundant pale-clear cytoplasm and undulating luminal borders
	Pink secretions with crystalloids	Corpora amylacea common
	Intraluminal blue mucin rare	Intraluminal blue mucin rare
High power	Nuclear atypia including prominent nucleoli	Lacks nuclear atypia and prominent nucleoli
Immunohistochemistry stains	Negative for basal cell makers, AMACR is variably positive	Positive for basal cell makers, AMACR is typically negative

PZ, Peripheral zone; TZ, transition zone.

Pathologic features ( Fig. 5.14 A–D)

Low-power architectural features

This lesion shows several crowded or haphazardly arranged large glands with branching and papillary infolding of the lumen. The large glands have tall columnar cells with abundant mildly amphophilic cytoplasm and basally located nuclei along the basement membrane. Often times associated with pink secretions within the lumen and crystalloids. Conventional acinar PAC is frequently present.

Fig. 5.14, An example of pseudohyperplastic carcinoma in needle biopsy. Note relatively deceptive, bland appearance of large glands at low power. Crowding, admixture with some small glands, and differences in cytoplasmic characteristics bring attention to these glands at low power (A) . At higher magnification, single layer of nuclei, with nuclear enlargement and prominent nucleoli, are visible (B, C) . The lack of basal cell markers (HMWCK and p63) in numerous glands along with strong internal control supports the diagnosis of pseudohyperplastic prostate carcinoma (D) . AMACR expression can be variable.

High-power cytologic features

Nuclear atypia in form of nuclear enlargement and prominent nucleoli is typically present and is required to make the diagnosis.

Immunohistochemical features

Basal cell markers are negative and AMACR is variably positive. The diagnosis requires the presence of several glands showing the above features. In a small focus, immunohistochemistry is not reliable.

9)

Foamy gland prostatic adenocarcinoma

Differential diagnosis: Xanthoma, cowper glands ( Table 5.9 )

Clinical features

Foamy gland PAC is a variant morphology of PAC. Typically occurs in the PZ. Well-formed foamy gland PAC may mimic Cowper glands, mucinous metaplasia, poorly formed adenocarcinoma, or xanthoma.

TABLE 5.9

Foamy Gland Prostatic Adenocarcinoma (PAC) Versus Cowper Glands Versus Xanthoma

	Foamy Gland PAC ( Fig. 5.15 A and B)	Cowper Glands ( Fig. 5.16 A and B)	Xanthoma ( Fig. 5.17 )
Location	PZ > TZ	Striated muscles of urogenital diaphragm lateral to the membranous urethra	PZ > TZ
Histologic features Low power	Abundant xanthomatous bubbly cytoplasm that resembles xanthoma cells. Intraluminal amorphous secretions are common. Conventional acinar PAC may be present	Lobulated collection of glands with abundant mucinous cytoplasm. Dimorphic appearance of central ducts surrounded by acini	Diffuse infiltration of xanthoma cells in small clusters or aggregates. Mixed inflammatory cell infiltrate common and provides a useful diagnostic clue. Cells lack glandular differentiation
	Architecturally, can vary from well-formed glands, nests, cords, and single cells	Smooth muscle cells commonly present
High power	Hyperchromatic pyknotic nuclei; mucin when present is luminal	Bland nuclei, mucin is intracellular	Bland nuclei
Immunohistochemistry stains	Negative for basal cell makers, AMACR is variably positive	Basal cells are retained, AMACR is negative	Positive for CD68, negative for keratins

PZ, Peripheral zone; TZ, transition zone.

Fig. 5.16, At low power, Cowper glands are composed of tightly circumscribed or lobulated proliferation of small, uniform acini lined by mucin-containing cells with a central duct. This dimorphic population of ducts surrounded by acini is a characteristic feature. Cytologic features are bland, including small nuclei and inconspicuous nucleoli. Mucin is present in the intracellular compartment in contrast to intraluminal mucin in prostate cancer (A) . Skeletal muscle is frequently present in the stroma (B) .

Fig. 5.17, In small needle biopsy samples, xanthomatous inflammation may mimic high-grade foamy carcinoma. Lack of any glandular differentiation, relatively bland nuclear features, and other inflammatory cells suggests the diagnosis of xanthomatous infiltrate. A panel of immunohistochemical markers of histiocytic lineage (CD68) and pancytokeratin may be necessary to rule out carcinoma.

Pathologic features ( Fig. 5.15 A and B)

Low-power architectural features

This lesion shows crowded or infiltrative glands with abundant xanthomatous bubbly cytoplasm that resemble xanthoma cells/histiocytes. Architecturally, can vary from well-formed glands, nests, cords, and single cells. Intraluminal amorphous secretions are common. Conventional acinar PAC is frequently present.

Fig. 5.15, At low power, a foamy gland carcinoma is characterized by abundant xanthomatous cytoplasm with low nuclear-to-cytoplasmic ratio, simulating a benign process. Intraluminal, dense, pink, acellular secretions are common. Conventional acinar differentiation is also common in foamy carcinoma. The nuclei are small and dense; typical malignant nuclear features of prostate cancer are only variably present (A) . A poorly differentiated foamy gland carcinoma simulating xanthomatous inflammation in needle biopsy. Presence of cytologic atypia and/or any glandular differentiation support the diagnosis of foamy gland carcinoma. An immunohistochemistry panel consisting of histiocytic markers and pancytokeratin may be needed to arrive at a definitive diagnosis in such cases, particularly in small needle biopsy samples (B) .

High-power cytologic features

A key cytologic feature is the presence of hyperchromatic pyknotic nuclei pushed to one side (typically basal). The overall nuclear-to-cytoplasmic (N:C) ratio is low, giving it a bland cytologic appearance. Intraluminal mucin may be present.

Immunohistochemical features

Basal cell markers are negative with variable positivity for AMACR. Negative for CD68.

10)

Intraductal carcinoma of the prostate

Differential diagnosis: Clear cell cribriform hyperplasia, high-grade prostatic intraepithelial neoplasia, intraductal spread of urothelial carcinoma, high-grade (cribriform) pac, ductal adenocarcinoma ( Table 5.10 )

Clinical features

Intraductal carcinoma of the prostate (IDC-P) is characterized by an expansile intraductal proliferation of malignant cells usually in dense cribriform or solid pattern. It typically represents a retrograde spread of associated high-grade and high-volume advanced PAC. Rarely, IDC-P may be identified in the absence of infiltrating carcinoma. Typically occurs in the PZ.

TABLE 5.10

Intraductal Carcinoma of the Prostate (IDC-P) Versus Clear Cell Cribriform Hyperplasia Versus High-grade Prostatic Intraepithelial Neoplasia (HGPIN) Versus High-grade (Cribriform) Prostatic Adenocarcinoma (PAC) Versus Ductal PAC Versus Intraductal Spread of Urothelial Carcinoma (UCa)

	IDC-P ( Fig. 5.18 A–C)	Clear Cell Cribriform Hyperplasia ( Fig. 5.20 )	HGPIN	High-Grade (Cribriform) PAC ( Fig. 5.21 )	Ductal PAC ( Fig. 5.22 )	Intraductal Spread of UCa ( Fig. 5.23 )
Location	PZ > TZ	TZ>PZ	PZ > TZ	PZ > TZ	Urethral mass or PZ when admixed with acinar PAC	TZ > PZ
Histologic features Low power	Medium- to large-caliber glands with expansile growth exhibiting frequent branching pattern	Numerous medium- to large-caliber cribriform glands with usually round contour in a pattern of nodular hyperplasia or rarely infiltrative	Glands of normal size with non-expansile growth	Small-, medium-, large-caliber glands with expansile growth	Large-caliber glands with expansile growth	Normal to expanded glands
	Comedo necrosis is a frequent finding	Necrosis absent	Necrosis absent	Can have necrosis	Can have necrosis	Can have necrosis
Architectural patterns	Dense cribriform, solid, loose cribriform, and rarely micropapillary	Glands lined by clear to mildly eosinophilic cytoplasm; glands exhibit roman bridges with nuclei streaming parallel to bridges	Tufted, flat, and micropapillary; cribriform architecture is typically not allowed in biopsy; such lesions often referred to as atypical intraductal proliferation	Cribriform glands of varying size and contour. Often confluent and infiltrative in nature. Solid nests and single cells if associated with a component of Gleason pattern 5	Cribriform, papillary and solid patterns; cribriform glands have slit-like compressed lumina	Solid nests with colonizing of high-grade cells
High power	Cytologic atypia present; Marked nuclear pleomorphism six times or greater than the size of a normal nucleus seen in subset of cases	Small bland nuclei with inconspicuous or small nucleoli; a strikingly prominent basal cell layer	Nuclei enlarged with prominent nucleoli, but lacks pleomorphism	Nuclear atypia present, but marked nuclear pleomorphism is uncommon	Columnar epithelium with elongated pseudostratified nuclei is a characteristic feature	Marked nuclear pleomorphism common
Immunohistochemistry stains	Positive for basal cell markers; variable AMACR positivity; PTEN loss and ERG overexpression in majority of cases	Positive for basal cell markers; negative for AMACR	Frequent patchy positive basal cells; variable AMACR positivity; intact PTEN; small subset with intermingling adjacent adenocarcinoma (18%) may express ERG	Negative for basal cell markers; positive for AMACR	Patchy retention of basal cells common in areas of intraductal growth; positive for AMACR; frequent ERG overexpression	Positive for p63 and GATA-3; negative for prostate-specific markers: PSA and NKX3.1

PZ, Peripheral zone; TZ, transition zone.

Fig. 5.20, Clear cell cribriform hyperplasia represents a spectrum of benign prostate hyperplasia and therefore is typically encountered in the transition zone of the prostate. In this transurethral resection specimen, there is a nodular proliferation of non-confluent large cribriform glands with clear to eosinophilic cytoplasm (A) . The cells forming the central lumina are cuboidal to low columnar secretory-type cells, with uniform round nuclei and clear cytoplasm. The glands are rimmed with a prominent basal cell layer (B) .

Fig. 5.21, In this prostate biopsy sample, many confluent atypical cribriform glands of varying size and shape are seen in an infiltrative pattern, suggestive of Gleason score 4 + 4 = 8. Basal cells to distinguish intraductal carcinoma of the prostate (IDC-P) from invasive cribriform glands should be utilized only when there is a concern whether the biopsy contains IDC-P only or when the Gleason grade could significantly change with the diagnosis of IDC-P.

Fig. 5.22, Ductal adenocarcinoma typically grows within preexisting ducts in cribriform and papillary patterns (prominent papillary pattern shown in this example). Glands and papillae are lined by tall pseudostratified columnar cells with elongated nuclei, a definitional feature. Basal cells may be preserved which should not be misinterpreted as high-grade prostatic intraepithelial neoplasia or intraductal carcinoma of the prostate .

Fig. 5.23, In urothelial carcinoma of the prostate, preexisting acini/ducts are expanded by high-grade pleomorphic cells without evidence of stromal invasion. Cytologic pleomorphism of tumor cells and scattered peripheral basal cells are visible (A) . This presentation mimics intraductal spread of high-grade prostate cancer. Strong reactivity for p63 in tumor cells supports the diagnosis of urothelial carcinoma; benign prostate glands demonstrate a peripheral layer of basal cells (B) .

Pathologic features ( Fig. 5.18 A–C)

Low-power architectural features

This lesion consists of medium- to large-caliber glands with expansile intraductal growth of carcinoma. Glands often have a branching pattern. Partial involvement of the gland is a common feature. Architectural growth patterns include dense cribriform (intraluminal cellular proliferation exceeding >50% of luminal space), solid, loose cribriform (intraluminal cellular proliferation <50% of luminal space), and rarely micropapillary. The presence of comedo necrosis in lesions with solid and/or dense cribriform is a frequent feature. Marked nuclear pleomorphism in some cases may be seen. In the presence of only loose cribriform or micropapillary architecture, the presence of non-focal comedo necrosis or marked nuclear pleomorphism is required to make the diagnosis. Borderline cases, specifically exhibiting loose cribriform growth or nuclear atypia that exceeds that of HGPIN but falls short of the diagnosis of IDC-P, should be referred to as AIP ( Fig. 5.19 ).

Fig. 5.18, A wide range of morphologic patterns may be seen in intraductal carcinoma, including loose cribriform, dense cribriform (cellular proliferation >50% of luminal spaces) with punched out or irregular lumina (A) , solid (B) , glands with comedo necrosis, partial involvement of benign gland, pleomorphic nuclei that are ≥6× of the adjacent nuclei and neoplastic cells exhibiting marked variation in nuclear size. For lesion lacking dense or solid architecture, the presence of either non-focal comedo necrosis or marked nuclear atypia is required to make the diagnosis of intraductal carcinoma. Glands are typically large and have branching architecture, a useful clue. Basal cells are usually visible but may require basal cell staining in some cases. Dense cribriform architecture is the most common presentation.

Fig. 5.19, Atypical intraductal proliferation (AIP) is morphologically more atypical than high-grade prostatic intraepithelial neoplasia (HGPIN) but lacks characteristic features of intraductal carcinoma of the prostate (IDC-P). Several glands present with lumen-spanning proliferation exhibiting loose cribriform architecture (luminal spaces account >50% of cellular proliferation) with morphologic features worse than HGPIN but falling short of IDC-P. AIP in biopsy should not be simply regarded as HGPIN, which may be conservatively followed. On the contrary, immediate repeat biopsy is warranted in this setting to rule out unsampled invasive carcinoma.

High-power cytologic features

Cytologic features include nuclear enlargement, hyperchromasia, and frequent prominent nucleoli. Marked nuclear pleomorphism that is six times or greater than the size of a normal nucleus is seen in some cases. Infrequently, dimorphic population of central small monomorphic cells and outer pleomorphic cells is present.

Immunohistochemical features

Basal cells are uniformly retained with variable AMACR positivity. PTEN loss and ERG overexpression are seen in majority of cases, and can be helpful in borderline cases in the differential of HGPIN.

11)

Ductal adenocarcinoma of the prostate

Differential diagnosis: Pin-like adenocarcinoma, high-grade prostatic intraepithelial neoplasia, papillary urothelial carcinoma ( Table 5.11 )

Clinical features

Ductal adenocarcinoma of the prostate typically occurs in 50s to elderly age range. It arises in the verumontanum in the prostatic urethra and underlying periurethral prostatic ducts but also commonly arises in the peripheral prostatic ducts and acini. When presenting as a urethral lesion, it typically is associated with gross or microscopic hematuria, dysuria, and frequency. Can be associated with a variable rise in PSA. Pure ductal adenocarcinoma is rare. Majority have a component of mixed ductal and acinar adenocarcinoma. Papillary and cribriform ductal adenocarcinoma is considered a Gleason pattern 4 or 5 if associated with necrosis. PIN-like ductal adenocarcinoma is considered Gleason pattern 3.

TABLE 5.11

Ductal Prostatic Adenocarcinoma (PAC) Versus Prostatic Intraepithelial Neoplasia (PIN)-like PAC Versus High-grade Prostatic Intraepithelial Neoplasia (HGPIN) Versus Papillary Urothelial Carcinoma (UCa)

	Ductal PAC ( Fig. 5.24 A and B)	PIN-like PAC ( Fig. 5.25 )	HGPIN	Papillary UCa
Location	Verumontanum and periurethral ducts Mixed acinar and ductal forms involve peripheral ducts	PZ > TZ	PZ > TZ	TZ > PZ
Histologic features Low power	Cribriform or papillary growth with true fibrovascular cores	Crowded proliferation of back-to-back darker than normal glands with frequent cystic dilatation	Scattered darker than normal glands with intraluminal proliferation	Papillary growth with true fibrovascular cores
Architectural patterns	Cribriform, papillary, and solid slit-like lumina	Tufted, flat, and micropapillary. Cribriform or papillary architecture is not compatible with the diagnosis. Strips of epithelium at the edge of the biopsy are a frequent finding and a useful clue to the diagnosis	Tufted, flat, and micropapillary. Rarely cribriform	Papillary fronds with high-grade cells
High power	Pseudostratified columnar nuclei with elongated nuclei; nuclear enlargement and prominent nuclei	PIN-like ductal adenocarcinoma have glands lined by elongated pseudostratified nuclei with hyperchromasia but lack prominent nucleoli; PIN-like acinar form has rounder nuclei and lack columnar appearance	Round enlarged nuclei with prominent nucleoli	Marked nuclear pleomorphism common
Immunohistochemistry stains	Can be positive for basal cell markers (in areas showing spread in ducts) or negative; variable AMACR positivity	Negative for basal cell markers; variable AMACR positivity	Patchy positive for basal cell markers; variable AMACR positivity	Positive for p63 and GATA-3; negative for prostate-specific markers: PSA and NKX3.1

PZ, Peripheral zone; TZ, transition zone.

Fig. 5.25, Prostatic intraepithelial neoplasia (PIN)–like adenocarcinoma appears as a focus of crowded large glands. Each individual cancer gland is large and has flat or irregular contours with tufted and micropapillary lumens lined with pseudostratified cells similar to high-grade prostatic intraepithelial neoplasia (HGPIN) glands (A) . However, cancer glands are more crowded than HGPIN. Nuclei are either round or elongated similar to ductal adenocarcinoma (B) . Some tumors show less prominent nucleoli than HGPIN. Cribriform or papillary architecture is not compatible with the diagnosis. Cancer glands are devoid of basal cells.

Pathologic features ( Fig. 5.24 A and B)

Low-power architectural features

This lesion consists of papillary, cribriform, or solid growth patterns. Papillary fronds and glands are lined by pseudostratified columnar epithelium. Glands often have slit-like compressed lumina.

Fig. 5.24, Ductal adenocarcinoma often grows within the urethra as a papillary or polypoid mass. The tumor often has prominent papillary, cribriform or solid architecture that is typically encountered in transurethral resection specimens where the distinction from urothelial carcinoma could be problematic (A) . Glands and papillae are lined by characteristic ductal epithelium and have prominent slit-like lumina (B) . An immunohistochemical panel of prostate and urothelial markers should be performed to rule out high-grade urothelial carcinoma. The tumor in this example is seen diffusely positive for NKX3.1 (C) .

High-power cytologic features

The cells lining papillae and cribriform glands have pseudostratified columnar epithelium with tall/elongated nuclei with cytologic atypia, a definitional feature of ductal differentiation. May show preservation of basal cell layer when arising or spreading in large ducts.

Immunohistochemical features

Can be positive for basal cell markers (in areas showing spread within ducts), an important pitfall that should not be misinterpreted as HGPIN. Variable AMACR positivity.

12)

Small cell (neuroendocrine) carcinoma

Differential diagnosis: Poorly differentiated urothelial carcinoma, poorly differentiated prostatic adenocarcinoma ( Table 5.12 )

Clinical features

Small cell carcinoma is a high-grade aggressive tumor defined by characteristic nuclear features. Approximately 40% to 50% of small cell carcinomas have a history of conventional PAC. The interval between the diagnosis of small cell carcinoma and prior conventional PAC ranges from 1 to 300 months with median of 25 months. Patients with this aggressive disease have frequent systemic disease and less often paraneoplastic syndromes. In cases of advanced disease, urinary obstructive symptoms and hematuria, in addition to distant metastases seen on imaging, may occur. Typically occurs in the PZ. Treatment includes multimodality therapy with platinum-based chemotherapy and ADT for associated conventional PAC. Small cell or large cell neuroendocrine (NE) carcinoma is not Gleason graded.

TABLE 5.12

Small Cell Carcinoma Versus Poorly Differentiated Urothelial Carcinoma (UCa) Versus Poorly Differentiated Prostatic Adenocarcinoma (PAC)

	Small Cell Carcinoma ( Fig. 5.26 )	Poorly Differentiated UCa	Poorly Differentiated PAC ( Fig. 5.27 A and B)
Location	PZ > TZ	Bladder neck	PZ > TZ
Histologic features Low power	Very blue due to high N:C ratio; geographic necrosis	Darker than normal glands	Eosinophilic appearance due to the low N:C ratio, relatively abundant cytoplasm
Architectural patterns	Sheets of cells without glandular differentiation	Lacks cribriform architecture; typically solid nests	Cribriform glands, large solid nests, and cords and sheets of cells
High power	Salt-and-pepper chromatin with lack of prominent nucleoli, nuclear molding, with very little cytoplasm	Nuclear pleomorphism with hyperchromasia	Nuclei with prominent nucleoli
	Numerous mitoses and apoptotic bodies	Increased mitotic figures with necrosis common	Can have variable mitotic figures and focal necrosis
Immunohistochemistry stains	Positive for at least one NE marker in over 90% of cases; high Ki-67 > 70%; PSA and other prostatic markers negative or only focally positive; p63 and high-molecular-weight cytokeratin positive in subset of cases. TTF1 frequently positive and does not differentiate primary from metastasis	Positive keratin, GATA-3, P63; variable AMACR positivity; negative for prostate markers	PSA and other prostate markers are typically retained and diffusely expressed, neuroendocrine markers can be variably positive, typically lack p63 and high-molecular-weight cytokeratins, Ki-67 < 50%

N:C ratio, Nuclear-to-cytoplasmic ratio; PZ, peripheral zone; TZ, transition zone.

Fig. 5.27, Poorly differentiated prostatic adenocarcinoma, Gleason score 5 + 5 = 10 in prostate biopsy with crush artifact, mimics small cell (neuroendocrine) carcinoma. Despite crush artifact, tumor cells exhibit relatively abundant cytoplasm and focal glandular differentiation (A) . Prostate-specific antigen was diffusely positive (B) . Focal neuroendocrine markers expression was noted and Ki-67 demonstrated moderate proliferation of about 40% (not shown).

Pathologic features ( Fig. 5.26 )

Low-power architectural features

This tumor is characterized by diffuse proliferation of sheets and nests of very blue cells with high N:C ratio, separated by geographic areas of necrosis. A starry sky pattern is common due to high cellular proliferation.

Fig. 5.26, Pure small cell carcinoma involving the prostate shows basophilic tumor cells arranged in haphazard nests and trabeculae. Cytologic features are identical to its pulmonary counterpart with scant cytoplasm, spindling of nuclei with salt-and-pepper chromatin, indistinct nucleoli, increased mitosis, apoptosis, and geographic areas of necrosis.

High-power cytologic features

Characteristic nuclear features include salt-and-pepper–type chromatin with lack of prominent nucleoli, nuclear molding, fragility, and crush artifact. High mitotic rate and apoptotic bodies are common. Morphologic variations include intermediate cell type with slightly more open chromatin and visible small nucleoli, seen in about 30% to 40% of cases.

Immunohistochemical features

Small cell carcinomas are positive for one or more NE markers (synaptophysin, chromogranin, CD56, INSM-1) in almost 90% of cases. PSA and other prostatic markers are typically negative or focally positive. In up to 30% of cases, positivity for basal cell markers can be present. TTF-1 is positive in up to 50% of cases. Ki-67 demonstrates high proliferation rate, typically >70%.

13)

Prostate stromal sarcoma

Differential diagnosis: Sarcomatoid carcinoma, gastrointestinal stromal tumor, malignant solitary fibrous tumor, leiomyosarcoma ( Table 5.13 )

Clinical features

Prostatic stromal sarcoma typically presents with lower urinary tract obstruction, abnormal digital rectal exam, and hematuria. Patients may exhibit symptoms of rectal fullness and/or a palpable rectal mass. Serum PSA levels are often within normal limits. Age of presentation is before the age of 50. Can occur in the PZ or TZ. Treatment includes radical prostatectomy; however, optimal therapy for metastatic disease is unknown.

TABLE 5.13

Prostatic Stromal Sarcoma Versus Sarcomatoid Carcinoma Versus Gastrointestinal Stromal Tumor (GIST) Versus Malignant Solitary Fibrous Tumor (SFT) Versus Leiomyosarcoma

	Prostatic Stromal Sarcoma ( Fig. 5.28 A and B)	Sarcomatoid Carcinoma ( Fig. 5.29 )	GIST ( Fig. 5.30 A and B)	Malignant SFT ( Fig. 5.31 )	Leiomyosarcoma ( Fig. 5.32 )
Location	PZ = TZ	TZ > PZ	Posterior of the prostate, arising from rectum or perirectal space. No convincing case of intraprostatic GIST reported	Most arise in prostate but can occur from secondary extension	Prostate or periprostatic mesenchymal elements
Gross features	Solid or partially cystic mass			Well circumscribed, firm with white-tan cut surface	Large, solid mass; may have cystic degeneration
Histologic features Low power	May resemble STUMP, however, intervening stroma is very hypercellular and shows stromal overgrowth with infiltration, hypercellularity, and EPE	Identifiable adenocarcinomatous and mesenchymal component	Fascicle or palisading growth pattern of cellular uniform spindle cells that lack pleomorphism and collagen deposition between tumor cells; biopsy typically lacks prostate glands	Ropey collagen and thick-walled irregular staghorn-shaped blood vessels	Sweeping intersecting fascicles of spindle cells, Lacks an adenocarcinomatous component
	Biphasic growth pattern resembling malignant phyllodes pattern with hypercellular mitotically active stroma with atypia; covered by benign-appearing prostate epithelium can be seen	Adenocarcinomatous component can be acinar, ductal, squamous, or small cell type		Patternless pattern	May have an epithelioid morphology
High power	Nuclear hyperchromasia and pleomorphism, mitotic activity, and necrosis. Epithelial component if present is typically benign in nature	High-grade spindle cells with or without heterologous elements and epithelioid component	Occasional perinuclear vacuoles	Haphazardly arranged spindled cells with oval nuclei and scant cytoplasm	Varying nuclear atypia, mitotic activity, and necrosis; can be low grade or high grade
Immunohistochemistry stains	Positive for CD34 and PR; variable positivity for SMA and desmin	Spindle cell component variably positive for keratins, especially HMWCK; p63 is a sensitive marker for epithelial differentiation in the spindle cell component; variably positive for PSA, PSAP, NKX3.1, SMA and desmin; negative for CD34	Positive for CD34; diffusely and strongly positive for CD117 (CKIT) and DOG1; S100, SMA and desmin are typically negative	Positive for CD34 and STAT6; negative for SMA and desmin; variable positivity for PR	Positive for SMA and desmin; one quarter of cases express cytokeratin (an important pitfall); p63 typically negative

EPE, Extraprostatic extension; PZ, peripheral zone; STUMP, stromal tumor of uncertain malignant potential; TZ, transition zone.

Fig. 5.29, Sarcomatoid carcinoma has high-grade undifferentiated spindle cell sarcoma with a myxoid background. Acinar carcinoma is present (arrows) and is intimately admixed with the sarcomaotid component. In contrast to prostate stromal sarcoma, epithelial component in sarcomatoid carcinoma is malignant. Extensive sampling is usually required to document the presence of the epithelial component. History of previous prostate carcinoma is also very useful to diagnose a sarcomatoid carcinoma and rule out primary sarcoma.

Fig. 5.30, Gastrointestinal stromal tumor (GIST) in a prostate core biopsy often represents rectal-based tumors that compress and displace the prostate gland. These GISTs, similar to other sites of origin, may have a variety of histologic patterns, including spindled and epithelioid morphology (A, B). The spindle cell morphology may have significant overlap with that of prostatic stromal proliferations, which are more common. Immunophenotypically, GISTs characteristically express CD34, CD117, and DOG-1. One must remember to consider this diagnostic possibility in prostate biopsies. GISTs involving the prostate gland should be evaluated using standard prognostic stratification proposed by WHO.

Fig. 5.31, Solitary fibrous tumor (SFT) involving the prostate gland demonstrates proliferation of bland spindle cells with a “patternless” pattern of stroma that is collagenized. Lack of admixed prostate glands and prominent collagen deposition in the stroma distinguishes it from a prostate stromal tumor. Vessels are abundant, hyalinized, and vary from small capillaries to characteristic larger hemangiopericytoma-like staghorn vessels. Strong and diffuse nuclear reactivity of STAT6 monoclonal antibody, suggestive of NAB2-STAT6 gene fusion, is characteristic and confirms the diagnosis of SFT.

Fig. 5.32, The transurethral resection of the prostate (TURP) specimen from a 58-year-old man demonstrated diffuse proliferation of high-grade spindle and epithelioid cells in a fascicular growth pattern. Some nuclei have a cigar shape and demonstrate frequent atypical mitoses. The differential diagnosis included prostatic stromal sarcoma, sarcomatoid carcinoma, and leiomyosarcoma. Tumor cells were diffusely and strongly positive for several muscle markers including desmin, calponin, and muscle-specific actin ( not shown ). The tumor cells also demonstrated focal aberrant reactivity for pan cytokeratin. The diagnosis of high-grade leiomyosarcoma was made.

Pathologic features ( Fig. 5.28 A and B)

Low-power architectural features

The tumor is characterized by hypercellular stroma. Stromal overgrowth, infiltration, and extraprostatic extension is frequently present. It can resemble stromal tumor of uncertain malignant potential (STUMP) with scattered atypical, but degenerative-appearing stromal cells. However, intervening stroma is too hypercellular for STUMP. Biphasic malignant phyllodes pattern with hypercellular mitotically active stroma with atypia covered by benign-appearing prostatic epithelium can also be present. Myxoid stroma is uncommon. Other patterns include: storiform, epithelioid, fibrosarcomatous, and patternless.

Fig. 5.28, In contrast to stromal tumor of uncertain malignant potential (STUMP), the prostatic stromal sarcoma demonstrates high cellularity (A) and obvious cytologic atypia with frequent mitoses (B) . Tumor cells may be seen proliferating between preexisting benign glands, similar to STUMP.

High-power cytologic features

Nuclear features of malignancy include marked nuclear pleomorphism, increased mitoses, necrosis, and apoptotic bodies. Epithelial component if present is typically benign in nature.

Immunohistochemical features

Immunohistochemical stains are generally not helpful with this diagnosis. Tumor cells are positive for CD34 and frequently for progesterone receptor (PR).

Bladder

1)

Urothelial carcinoma in situ

Differential diagnosis: Reactive urothelial atypia, radiation/chemotherapy urothelial atypia ( Table 5.14 )

Clinical features

Primary or de novo urothelial carcinoma in situ (CIS) is exceedingly rare. It is typically detected with a high-grade urothelial carcinoma (UCa) component. Most commonly seen in the sixth or seventh decade of life. Patients may present asymptomatically, or with dysuria, nocturia, and microscopic hematuria. Cystoscopic appearance can range from normal, to frequently erythematous velvety lesion, to edematous or erosive. It commonly presents as multifocal disease.

TABLE 5.14

Carcinoma In Situ (CIS) Versus Reactive Urothelium Versus Radiation/Chemotherapy (RT/CT) Urothelial Atypia

	CIS ( Fig. 5.33 A–C)	Reactive Urothelium ( Fig. 5.34 )	RT/CT Urothelial Atypia ( Fig. 5.35 A and B)
Cystoscopic features	Flat lesion with erythematous, edematous, or erosive appearance	Flat lesion with erythematous, edematous, or erosive appearance	Flat lesion with erythematous, edematous, or erosive appearance
Histologic features Low power	Morphologic patterns include: pleomorphic, pagetoid, “clinging” or denuding, small cell, plasmacytoid type	Degree of reactive changes proportional to extent of inflammation	Flat mucosa and von Brunn nests exhibit marked random and degenerative-type atypia
	Loss of cellular cohesion and polarity to basement membrane common	Intraepithelial inflammation is prominent. Cellular cohesion and polarity maintained	Surrounding stroma shows reactive changes including hemorrhage, fibrin thrombi, and atypical stromal cells. Cellular cohesion and polarity maintained
	Thickness variable	Thickness variable	Thickness variable
High power	Nucleomegaly more than five times normal lymphocyte nucleus	Enlarged nuclei	Nuclei are bizarre with multinucleation and vacuolization
	Coarse, condensed nuclear chromatin	Nuclei uniform in size and shape, nuclei vesicular with central prominent nucleoli.	Nuclei often have degenerative atypia, cytoplasm abundant with spindled appearance
	Mitoses variable, with atypical forms that frequently present in upper layer	Mitotic figures may be numerous, lacks atypical mitoses	Mitoses variable, lacks atypical mitosis
Immunohistochemistry stains	CK20 full thickness positivity; CD44 negative or restricted to basal cells; p53 aberrant expression is specific but lacks sensitivity	CK20 confined to the umbrella cell layer; CD44 positive in basal and upper layers	CK20 confined to the umbrella cell layer; CD44 positive in basal and upper layers

Fig. 5.34, In reactive urothelial atypia, polarity of cells is well maintained. Nuclei are uniformly enlarged with vesicular chromatin and single prominent nucleoli. Numerous intramucosal neutrophils are present with background inflammation.

Fig. 5.35, In treatment-induced cytologic atypia, polarity of cells is maintained. Nuclei show random degenerative-type marked cytologic atypia. Stroma shows reactive changes (A) . Cells have abundant often vacuolated cytoplasm with frequent multinucleation. Mitotic activity, specifically atypical forms, not seen (B) .

Pathologic features ( Fig. 5.33 A–C)

Low-power architectural features

Urothelial CIS has various morphologic patterns: pleomorphic, pagetoid, “clinging” (denuding), small cell, and plasmacytoid. Urothelial thickness varies from denuded to normal to hyperplastic. Loss of cellular cohesion and polarity is frequently observed.

Fig. 5.33, A , In carcinoma in situ (CIS), cells are discohesive with markedly enlarged hyperchromatic nuclei relative to stromal lymphocytes. Nuclei are variable in size and shape. Mitosis including atypical forms are seen. B , CIS with marked denudation of urothelium. Remaining cells are loosely cohesive with markedly enlarged and hyperchromatic cells, characteristic of “clinging” or “denuding” type. C , In pagetoid CIS, few markedly atypical cells with abundant cytoplasm are seen dispersed throughout otherwise a normal-appearing epithelium.

High-power cytologic features

There is marked nucleomegaly of more than five times the size of a normal lymphocyte nucleus. Nuclear chromatin is coarse, condensed with frequent pleomorphism. Mitoses are variable, with atypical forms, frequently extending to the upper layer of urothelium. A strict diagnostic threshold is maintained for this diagnosis. For a lesion that appears worse than reactive/inflammatory atypia but falls short of diagnostic criteria of CIS, the diagnosis of dysplasia should be considered in the differential. The term flat urothelial atypia of unknown significance is utilized when cytologic atypia cannot be distinguished between dysplasia from a reactive/inflammatory process.

Immunohistochemical features

CK20 demonstrates full-thickness positivity. Full-thickness staining does not distinguish dysplasia from CIS. Additionally, loss of CD44 expression or expression confined to the basal cell layer is seen. P53 aberrant expression (diffuse positive or null phenotype) is a specific staining pattern of CIS but lacks sensitivity. Immunohistochemical markers are not helpful in differential of dysplasia from CIS.

2)

Low-grade papillary urothelial carcinoma

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