Feature	Description	Clinical/Pathological Relevance
Location	Retroperitoneal, inferior to the bladder, anterior to the rectum, superior to the urogenital diaphragm. Surrounds the prostatic urethra.	Proximity to rectum is important for DRE and TRUS biopsy. Bladder neck involvement is a staging consideration for cancer.
Size & Weight	Approx. 3-4 cm (length) x 4-5 cm (width) x 2-3 cm (AP). Normal weight: typically 20-30 grams.	Increases with age, primarily due to Benign Prostatic Hyperplasia (BPH). Weight is noted in surgical pathology reports.
Zonal Anatomy (McNeal)	Crucial for understanding pathology distribution:
	Peripheral Zone (PZ) Makes up most of the glandular tissue. Posterior and lateral aspects.	Site of most prostatic adenocarcinomas. Palpable on DRE. Target for biopsies.
	Transition Zone (TZ) A smaller portion of glandular tissue. Surrounds urethra proximal to ejaculatory ducts.	Site of Benign Prostatic Hyperplasia (BPH). Site of some adenocarcinomas.
	Central Zone (CZ) A portion of glandular tissue. Surrounds ejaculatory ducts, posterior to urethra, forms base of prostate.	Resistant to carcinoma and hyperplasia. Tumors here are less common. Histologically distinct from PZ and TZ.
	Anterior Fibromuscular Stroma (AFS) A minor component of prostate volume. Non-glandular; smooth muscle and fibrous tissue.	Primarily non-glandular; not a site of adenocarcinoma, but can be involved by extension or have mesenchymal tumors.
"Capsule"	Fibromuscular band surrounding the prostate; it's a pseudocapsule, not a true histological capsule. Incomplete, especially at apex.	Important for staging of prostate cancer (Extraprostatic Extension - EPE).
Base	Superior aspect, adjacent to the bladder.	Surgical margin assessment in radical prostatectomy.
Apex	Inferior aspect, adjacent to the urogenital diaphragm.	Surgical margin assessment. Higher risk of positive margins.
Verumontanum	Eminence on the posterior wall of the mid prostatic urethra where ejaculatory ducts and prostatic utricle open.	Anatomical landmark.
Ejaculatory Ducts	Pass through the central zone to join the prostatic urethra at the verumontanum.	Lined by pseudostratified columnar epithelium, can be involved by CZ tumors or show benign changes.
Vasculature	Arteries: Inferior vesical, middle rectal, internal pudendal. Veins: Prostatic venous plexus (to internal iliac veins).	Perineural invasion often follows nerve routes which are associated with vasculature.
Lymphatics	Obturator, internal iliac, external iliac, sacral nodes.	Important for patterns of metastatic spread.

Feature	Description & Key Identifiers (IHC in brackets)	Relevance / Pitfalls
General Glandular Architecture	Acini/glands embedded in fibromuscular stroma.	Disruption of normal architecture is a key feature of malignancy.
1. Luminal (Secretory) Cells	- Single layer of columnar to cuboidal cells lining the lumen. - Abundant eosinophilic, granular cytoplasm. - Round to oval nuclei, usually uniform; nucleoli can be visible but are typically small and not prominent/irregular in benign glands. - Secretions: PSA, Prostatic Acid Phosphatase (PAP), PSMA. - [IHC: PSA+, PAP+, PSMA+, CK8/18+]	Cytoplasmic pallor/clearing can be seen (e.g., clear cell hyperplasia). Nuclear atypia (enlargement, prominent nucleoli) is a hallmark of adenocarcinoma. PSA/PAP stains tumor cells.
2. Basal Cells	- Layer of cuboidal or flattened cells situated between luminal cells and basement membrane. - Scant cytoplasm, indistinct cell borders. - Oval to spindle-shaped, darker nuclei. - [IHC: CK5/6+, HMWCK (34βE12)+, p63+, p40+] (GATA3 also stains basal cells strongly, but also luminal cells more weakly).	Crucial for distinguishing benign from malignant glands. Prostatic adenocarcinoma characteristically lacks basal cells. Some high-grade PIN may show attenuated/patchy basal cells.
3. Neuroendocrine (NE) Cells	- Scattered cells, often near basal layer. - Eosinophilic to clear cytoplasm, fine granular chromatin. - [IHC: Chromogranin A+, Synaptophysin+, CD56+]	May be increased in BPH, inflammation, or adjacent to cancer. Pure neuroendocrine carcinomas are rare but aggressive. Not directly involved in typical adenocarcinoma pathogenesis.
Stroma	- Composed of smooth muscle and fibroblasts. - Separates and supports glands.	Stromal proliferation is a major component of BPH. Stromal invasion is a feature of cancer. Reactive stroma can be seen in inflammation or around cancer.
Zonal Histological Differences:
Peripheral Zone (PZ)	- Glands are typically small, round, simple, and relatively loosely packed. - Stroma is loose fibromuscular tissue.	Most common site for adenocarcinoma and prostatitis. Atrophy is common.
Transition Zone (TZ)	- Variable glandular architecture; can be similar to PZ or show nodular hyperplasia (BPH) with papillary and cribriform patterns. - More prominent stroma, especially in BPH nodules.	Site of BPH. Cancers here can be more difficult to detect.
Central Zone (CZ)	- Glands are larger, more architecturally complex, irregular, with intraluminal undulations, papillae, and bridging. - Luminal cells often have more abundant, deeply eosinophilic cytoplasm. - Stroma is denser, more compact fibromuscular tissue with thicker smooth muscle bundles.	Distinct histology; resistant to cancer. Can be confused with high-grade PIN or cribriform adenocarcinoma if not familiar with normal CZ features. Basal cells are present.
Anterior Fibromuscular Stroma (AFS)	- Predominantly dense fibromuscular tissue (smooth muscle and collagen) with very few or no glands.	Not a primary site of glandular pathology but can be involved by extensive disease.
Other Common Structures/Features
Corpora Amylacea	- Eosinophilic, laminated, acellular concretions within gland lumina. - May calcify.	Common, especially with age. No clinical significance.
Prostatic Urethra Lining	- Transitional epithelium (urothelium).	Can be involved by urothelial carcinoma or by direct extension of prostate cancer.
Important Benign Variations & Potential Mimics
Prostatic Atrophy	- Glands are small, shrunken, with scant cytoplasm. - Simple Atrophy: Small, crowded glands, dark nuclei, but preserved basal cells. - Sclerotic/Cribriform Atrophy (Post-Atrophic Hyperplasia): Small, closely packed glands, sometimes with cribriform appearance; basal cells present. Cytologically bland.	Can mimic low-grade adenocarcinoma. Key: Presence of basal cells (HMWCK, p63). Inflammation often present.
Basal Cell Hyperplasia (BCH)	- Proliferation of basal cells, leading to thickened basal cell layer or solid nests/nodules. - Various patterns: typical, adenoid basal, cribriform. - [IHC: Strong p63/HMWCK+]	Solid or cribriform patterns can mimic adenocarcinoma or intraductal carcinoma. Key: Strong and diffuse basal cell marker expression. Lacks atypia of luminal cells.
Adenosis (Atypical Adenomatous Hyperplasia)	- Localized proliferation of small, crowded glands. - Luminal cells are cytologically bland; nucleoli may be visible but not prominent. - Basal cells are present and usually identifiable.	Can be difficult to distinguish from well-differentiated adenocarcinoma on H&E alone. Key: Confirmation of basal cell layer. PSA/AMACR can be helpful (AMACR typically negative/patchy vs. diffuse in cancer).
Inflammation	- Acute (neutrophils) or chronic (lymphocytes, plasma cells). - Can be focal or diffuse.	Can cause reactive atypia in epithelial cells, potentially mimicking malignancy. Granulomatous prostatitis can mimic TB or fungal infection, or high-grade cancer on imaging/DRE.
Seminal Vesicle (SV) / Ejaculatory Duct (ED) Tissue	- SV: Complex papillary glands, pseudostratified epithelium with marked nuclear atypia (pleomorphism, hyperchromasia - "monster cells"), lipofuscin pigment in cytoplasm. No basal cell layer. [IHC: PSA/PAP negative]. - ED: Complex architecture, similar epithelium to SV, often with less atypia.	SV tissue in a needle biopsy can be mistaken for high-grade prostate cancer due to atypia. Key: Lipofuscin, PSA/PAP negativity.
Cowper's (Bulbourethral) Glands	- Lobules of mucinous acini near prostatic apex/urogenital diaphragm. - Clear, abundant mucinous cytoplasm; small, basally located nuclei. - [IHC: PSA/PAP negative].	Can be present in apical prostate sections or biopsies and mistaken for foamy gland variant of adenocarcinoma or mucinous adenocarcinoma. Key: Mucin quality, PSA negativity.
Clear Cell Cribriform Hyperplasia	- Cribriform glands lined by cells with clear cytoplasm and bland nuclei. - Maintains a basal cell layer.	Can mimic cribriform prostate cancer or intraductal carcinoma. Key: Bland cytology and intact basal cell layer.

Histology & Anatomy of Adrenal Gland Cortex

Feature	Description	Clinical/Pathological Relevance
Location	Paired endocrine glands located superior and medial to the kidneys, retroperitoneal.	Surgical accessibility, relationship to kidney.
Shape	Right: Pyramidal or V-shaped. Left: Semilunar or crescentic.	Anatomical landmark during grossing or imaging.
Size	Approx. 4-6 cm in length, 2-3 cm in width, 0.4-0.8 cm in thickness (variable).	Changes in size can indicate hyperplasia, atrophy, or tumors.
Weight	Combined weight: approx. 8-12 grams (each gland 4-6 grams). Weight is variable.	Increased weight can suggest hyperplasia or neoplasm. Low weight can suggest atrophy.
Gross Appearance	Flattened, encapsulated. Cut surface shows a bright yellow outer cortex and a thinner, gray-tan inner medulla.	Color of cortex is due to lipid content. Medulla may be difficult to distinguish grossly in some cases or may appear hemorrhagic.
Blood Supply	Richly vascular. Arterial supply from superior, middle, and inferior suprarenal arteries. Venous drainage via a single central adrenal vein (right to IVC, left to left renal vein).	Important for understanding metastatic patterns and surgical considerations. The single large vein is a key surgical landmark.
Structure	Composed of an outer cortex and an inner medulla. This overview focuses on the cortex.	Cortex and medulla have different embryological origins and functions.
Cortex Layers	Grossly, the cortex is a yellow rim. Histologically, it is divided into three zones.	Each zone produces different steroid hormones.

Zone	Location & Proportion	Cellular Arrangement & Morphology	Cytoplasmic Features	Key Hormones Produced	Relevant Notes / Potential Pitfalls
1. Zona Glomerulosa (ZG)	Outer zone, directly beneath the capsule. A relatively thin layer.	- Rounded or arched clusters/acini of cells. - Cells are relatively small, columnar or pyramidal. - Nuclei are round, densely staining.	- Scant to moderate amount of eosinophilic cytoplasm. - Fewer lipid droplets compared to ZF.	Mineralocorticoids (primarily Aldosterone)	- May be inconspicuous or hyperplastic. - Aldosterone-producing adenomas arise from this zone or have ZG-like cells. - "Spironolactone bodies" (eosinophilic, laminated cytoplasmic inclusions) can be seen with spironolactone treatment.
2. Zona Fasciculata (ZF)	Middle zone. Makes up the largest part of the cortex (most of its thickness).	- Long, straight cords or columns of cells (fascicles), typically 1-2 cells thick, separated by sinusoidal capillaries. - Cells are large, polyhedral. - Nuclei are central, vesicular.	- Abundant, pale-staining, foamy, or vacuolated cytoplasm ("clear cells") due to numerous lipid droplets (cholesterol).	Glucocorticoids (primarily Cortisol)	- Lipid depletion can occur with stress, making cells more eosinophilic ("compact cells"), resembling ZG or ZR cells. - Site of most cortical adenomas and carcinomas (often with ZF-like cells). - Cytomegaly can be a normal finding in pediatric adrenals.
3. Zona Reticularis (ZR)	Inner zone, adjacent to the adrenal medulla. A relatively thin, irregular layer.	- Anastomosing cords or irregular clusters of cells. - Cells are generally smaller than ZF cells, more variable in size. - Nuclei often appear more hyperchromatic.	- Eosinophilic to granular cytoplasm ("compact cells"). - Fewer lipid droplets than ZF. - Lipofuscin pigment is common and increases with age, giving a brownish hue.	Androgens (e.g., Dehydroepiandrosterone - DHEA, Androstenedione) and some Glucocorticoids.	- Boundary with ZF can be indistinct. - Cells can appear more "atypical" or pleomorphic, especially with age, which is a normal finding. - Can be difficult to distinguish from inner ZF cells, especially if ZF cells are lipid-depleted.
General Cortical Features		- Cells are polygonal with eosinophilic to clear cytoplasm depending on lipid content. - Rich sinusoidal network.	- Lipid content varies by zone and physiological state.	Steroid hormones	- Accessory adrenocortical rests/nodules can be found outside the adrenal gland (e.g., near kidney, gonads). - Age-related changes: increased lipofuscin in ZR, cortical nodules (often non-functional).

Histology & Anatomy of Urinary Bladder

Feature	Description	Clinical/Pathological Relevance
Location	Pelvic organ. Anterior in males; anterior to vagina and uterus in females. Retroperitoneal (superior surface covered by peritoneum).	Proximity to other organs is important for local spread of tumors and surgical approaches.
Shape & Capacity	Hollow, distensible, muscular organ. Shape varies with urine volume (empty: tetrahedral; full: ovoid). Average capacity: 400-600 mL.	Overdistension or chronic obstruction can lead to hypertrophy and trabeculation.
Major Parts	Apex: Anterosuperior, points towards pubic symphysis, connected to umbilicus by median umbilical ligament (urachal remnant). Body/Dome: Main part. Base (Fundus): Posteroinferior, triangular area. Trigone: Smooth triangular area at the base, bounded by the two ureteric orifices and the internal urethral orifice. Neck: Most inferior part, continuous with urethra.	The trigone has distinct embryological origin (mesodermal) and histology (thinner urothelium, less distinct muscle layers initially). Urachal remnants at the apex can give rise to adenocarcinomas.
Wall Layers	From lumen outwards: 1. Mucosa (Urothelium + Lamina Propria) 2. Muscularis Propria (Detrusor muscle) 3. Serosa / Adventitia	Depth of tumor invasion through these layers is critical for staging bladder cancer (T stage).
Vasculature	Arterial: Superior and inferior vesical arteries (branches of internal iliac artery). Some supply from obturator and inferior gluteal arteries. Venous: Vesical venous plexus, drains into internal iliac veins.	Understanding blood supply is important for surgical procedures and patterns of hematogenous spread.
Lymphatics	Drain primarily to external iliac, internal iliac, and obturator lymph nodes. Some drainage to common iliac nodes.	Crucial for staging metastatic disease. Lymph node dissection is part of radical cystectomy for invasive cancer.
Innervation	Autonomic nervous system: Parasympathetic (pelvic splanchnic nerves, S2-S4): Motor to detrusor (contraction for micturition), inhibitory to internal sphincter. Sympathetic (hypogastric nerves, T11-L2): Inhibitory to detrusor, motor to internal sphincter (promotes filling). Somatic (pudendal nerve): External urethral sphincter.	Nerve involvement by tumors can cause pain or functional deficits. Knowledge is important for understanding bladder dysfunction.

Feature	Description & Key Identifiers (IHC in brackets)	Relevance / Pitfalls / Benign Variations
1. Urothelium (Transitional Epithelium)	- Lines the lumen. Normally 3-7 cell layers thick (distension dependent). - Basal Layer: Single layer of small, cuboidal to columnar cells with scant cytoplasm, higher N/C ratio, oriented perpendicular to basement membrane. - Intermediate Layer(s): Multiple layers of polygonal to columnar cells that mature towards the surface. - Umbrella Cell Layer (Superficial Layer): Large, flattened, often multinucleated cells with abundant eosinophilic cytoplasm, scalloped luminal border. Prominent nucleoli can be normal. Asymmetric unit membrane (uroplakin plaques). - [IHC: CK7+, CK20+ (mainly umbrella cells), GATA3+, p63+ (basal/intermediate), Uroplakin+ (umbrella cells)]	- Key for diagnosis of urothelial carcinoma. Thickness varies; thin in trigone. - Reactive Atypia: Can show enlarged nuclei, prominent nucleoli, mitoses, especially with inflammation or instrumentation. Must distinguish from dysplasia/CIS. Umbrella cells usually maintained. - Denudation: Loss of urothelium common with inflammation/instrumentation.
Benign Urothelial Variations/Lesions	- Von Brunn Nests: Solid nests of bland urothelial cells within lamina propria, often connected to surface urothelium. - Cystitis Cystica: Von Brunn nests with central cystic degeneration (lumen formation). - Cystitis Glandularis: Cystitis cystica where lining cells undergo glandular (mucinous or intestinal-type) metaplasia. - Nephrogenic Adenoma: Papillary or tubular proliferation of small cuboidal cells, often hobnail, associated with chronic irritation/injury. [IHC: PAX8+, GATA3+, AMACR+] - Squamous Metaplasia: Replacement by squamous epithelium; non-keratinizing common in trigone (females), keratinizing is abnormal. - Intestinal (Colonic) Metaplasia: Replacement by intestinal-type epithelium with goblet cells.	- Von Brunn nests, cystitis cystica/glandularis are common, benign findings; distinguish from invasive carcinoma (especially nested variant). Cytologically bland. - Nephrogenic adenoma can mimic clear cell carcinoma or prostatic adenocarcinoma. - Extensive keratinizing squamous metaplasia or intestinal metaplasia can be associated with increased risk of carcinoma.
2. Lamina Propria (LP)	- Loose fibroconnective tissue layer beneath the urothelium. - Contains blood vessels, lymphatics, nerves, scattered inflammatory cells. - Muscularis Mucosae (MM): Discontinuous, wispy smooth muscle bundles; may be absent or prominent. Not the muscularis propria. Usually thinner and more irregular than MP bundles.	- Crucial for staging: Invasion into LP (pT1) is a key prognostic factor. - Presence and status of MM can be debated in its utility for sub-staging pT1 tumors. If present, it helps define the LP. - Increased vascularity or inflammation is common.
3. Muscularis Propria (MP) (Detrusor Muscle)	- Thick bundles of smooth muscle. - Classically described as three layers (inner longitudinal, middle circular, outer longitudinal), but often appear interwoven and haphazard, especially in biopsies. - Interspersed with connective tissue and vessels.	- Definitive invasion into MP (pT2) is a critical staging parameter, significantly impacting treatment and prognosis. - Distinguishing hypertrophied MM from MP invasion in fragmented TURBT specimens can be challenging. Look for thick, well-organized bundles for MP.
4. Adventitia / Serosa	- Adventitia: Outer layer of loose connective tissue, vessels, nerves, adipose tissue (covers most of bladder). - Serosa: Thin layer of connective tissue covered by mesothelium (peritoneum); found only on the superior and parts of the posterosuperior surface of the bladder.	- Invasion into perivesical fat (pT3a) or serosa (pT3b if covered by peritoneum) is important for staging.
Other Structures	- Paraganglia: Small clusters of neuroendocrine cells (chief cells and sustentacular cells) may be found in the bladder wall, especially lamina propria or perivesical tissue. [IHC: Chromogranin+, Synaptophysin+, S100+ (sustentacular)]. - Interstitial Cells of Cajal-like cells: Can be found in lamina propria and muscularis propria.	- Paraganglia are benign; distinguish from paraganglioma or neuroendocrine carcinoma. - Understanding normal variants helps avoid misdiagnosis.

Histology & Anatomy of Seminal Vesicles & Ejaculatory Ducts

Feature	Description	Clinical/Pathological Relevance
Seminal Vesicles (SV)	Paired, elongated, lobulated, glandular structures located posterior to the bladder and superior-posterior to the prostate. Each joins the ampulla of the vas deferens to form the ejaculatory duct.	Can be involved by prostate cancer or be the site of primary tumors (rare). Normal SV tissue in a prostate biopsy can mimic cancer.
	Size: Approx. 5 cm long (but coiled, appearing smaller).	Volume/size not typically a primary diagnostic feature unless grossly abnormal.
Ejaculatory Ducts (ED)	Formed by the union of the seminal vesicle duct and the ductus (vas) deferens. Paired structures that pass through the central zone of the prostate to open into the prostatic urethra at the verumontanum.	Can be obstructed or involved by prostatic pathology. Their path through the central zone is important.

Structure	Epithelium	Stroma & Other Features	IHC & Key Distinctions
Seminal Vesicles (SV)	- Pseudostratified columnar epithelium with complex papillary fronds and bridging architecture. - Cells often show marked nuclear atypia (pleomorphism, hyperchromasia, prominent nucleoli) which is normal ("symplastic" or "pseudosarcomatous" atypia). - Abundant eosinophilic cytoplasm, often containing golden-brown lipofuscin pigment.	- Thin fibromuscular stroma supporting the glands. - Lumen contains eosinophilic, proteinaceous secretions (fructose-rich).	- Crucially PSA and PAP negative or only very weakly/focally positive. - No basal cell layer. - Lipofuscin is a key feature. - Atypia + lack of PSA/PAP helps distinguish from prostatic adenocarcinoma. GATA3 can be positive.
Ejaculatory Ducts (ED)	- Similar to seminal vesicles but may be less complex; pseudostratified columnar epithelium. - Cellular atypia and lipofuscin are generally less prominent than in SVs but can be present.	- Surrounded by fibromuscular stroma of the prostate's central zone.	- Generally PSA and PAP negative. - Presence within prostatic tissue is normal.

Histology & Anatomy of Penis & Scrotum

Feature	Description	Clinical/Pathological Relevance
Major Components	- Corpora Cavernosa (paired): Dorsolaterally located erectile bodies. - Corpus Spongiosum (single): Ventrally located erectile body surrounding the urethra, expands distally to form the glans. - Glans Penis: Distal expansion of corpus spongiosum. - Prepuce (Foreskin): Retractable fold of skin covering the glans (in uncircumcised males). - Tunica Albuginea: Dense fibrous sheath surrounding each corpus cavernosum and, more thinly, the corpus spongiosum.	Understanding these structures is key for staging penile cancers and understanding erectile function.
Urethra	Penile (spongy) urethra passes through the corpus spongiosum.	Site of primary urethral lesions or involvement by penile tumors.

Structure	Epithelium	Underlying Tissue & Features
Skin of Shaft	Keratinized stratified squamous epithelium.	Dermis with hair follicles, sebaceous glands, sweat glands (eccrine and apocrine). Subcutaneous tissue (dartos fascia).
Glans Penis	Thin stratified squamous epithelium; typically non-keratinized or minimally keratinized. Richly innervated.	Highly vascular lamina propria (corpus spongiosum tissue). Specialized sensory nerve endings (e.g., Meissner's corpuscles). Lacks hair follicles and sweat glands.
Prepuce (Foreskin)	- Outer surface: Keratinized stratified squamous epithelium (skin). - Inner mucosal surface: Thin, non-keratinized (or lightly keratinized) stratified squamous epithelium.	- Outer: Dermis with skin adnexa. - Inner: Lamina propria, Tyson's glands (modified sebaceous glands) may be present near coronal sulcus.
Corpora Cavernosa & Corpus Spongiosum	Endothelium-lined vascular spaces (sinusoids).	Separated by trabeculae of smooth muscle and connective tissue. Encased by tunica albuginea. Corpus spongiosum has more elastic fibers and less muscle than cavernosa.
Tunica Albuginea	N/A (Connective tissue)	Dense fibroconnective tissue.

Histology & Anatomy of Male Urethra

Segment	Location & Approx. Length	Key Features
Prostatic Urethra	Passes through the prostate gland from bladder neck to apex of prostate. (Approx. 3-4 cm)	Widest, most dilatable part. Verumontanum (colliculus seminalis) on posterior wall with openings of ejaculatory ducts & prostatic utricle.
Membranous Urethra	Passes through the urogenital diaphragm (external urethral sphincter). (Approx. 1-2 cm)	Narrowest and least distensible part. Surrounded by skeletal muscle of external sphincter.
Bulbous Urethra	Begins distal to urogenital diaphragm, within the bulb of penis (corpus spongiosum). (Variable length)	Openings of bulbourethral (Cowper's) glands.
Penile Urethra (Spongy/Pendulous)	Passes through the corpus spongiosum to the external urethral meatus. (Approx. 15 cm, variable)	Longest segment. Glands of Littré open into this segment. Fossa navicularis is a distal dilatation just before the meatus.

Segment	Lining Epithelium	Periurethral Structures / Lamina Propria
Prostatic Urethra	Urothelium (Transitional Epithelium), similar to bladder.	Lamina propria surrounded by prostatic tissue.
Membranous Urethra	Primarily urothelium proximally, may transition to pseudostratified or stratified columnar epithelium distally.	Surrounded by striated muscle of the external urethral sphincter.
Bulbous & Penile Urethra (Proximal to Fossa Navicularis)	Primarily pseudostratified or stratified columnar epithelium. Patches of urothelium can be present.	Lamina propria is vascular connective tissue. Surrounded by corpus spongiosum. Glands of Littré (small, mucinous periurethral glands) present in lamina propria/submucosa.
Fossa Navicularis & External Meatus	Stratified squamous epithelium (non-keratinized).	Lamina propria.

Histology & Anatomy of Testis & Epididymis

Feature	Description	Clinical/Pathological Relevance
Testis - General	Paired, ovoid male gonads responsible for spermatogenesis and androgen production. Located within the scrotum.	Site of germ cell tumors, sex cord-stromal tumors, and various inflammatory/vascular conditions.
Testis - Size & Weight	Adult: Approx. 3.5-5.5 cm length, 2.5-3.5 cm width, 3 cm AP diameter. Volume typically 15-30 mL. Weight approx. 10-30 grams each. Varies with age and individual.	Size can be affected by atrophy, hormonal status, or tumors. Important baseline for assessing pathology.
Testis - Coverings	- Tunica Vaginalis: Serous membrane (mesothelial lining) covering the anterior and lateral aspects. Derived from peritoneum. Has parietal and visceral layers. - Tunica Albuginea: Dense, white, inelastic fibrous capsule directly covering the testis. - Tunica Vasculosa: Inner vascular layer of the tunica albuginea.	Hydroceles occur within the tunica vaginalis. Tunica albuginea is key for staging testicular tumors (invasion is significant).
Testis - Internal Structure	- Septa: Tunica albuginea gives rise to fibrous septa that divide the testis into numerous (approx. 250-400) lobules. - Seminiferous Tubules: Each lobule contains 1-4 coiled seminiferous tubules. - Mediastinum Testis: A mass of fibrous tissue at the posterior aspect of the testis, formed by the convergence of the tunica albuginea. The rete testis is located here.	Understanding lobular architecture and the path of sperm.
Rete Testis	Anastomosing network of channels located within the mediastinum testis. Seminiferous tubules drain into the rete testis via tubuli recti (straight tubules).	Connects seminiferous tubules to efferent ductules. Can be involved by tumors or inflammation.
Efferent Ductules	Approx. 10-20 small ducts that connect the rete testis to the head of the epididymis.	Transport sperm from rete testis to epididymis. Lined by ciliated and non-ciliated columnar cells.
Epididymis - General	Single, tightly coiled tube (approx. 4-6 meters long if uncoiled) located on the posterolateral aspect of the testis. Divided into head (caput), body (corpus), and tail (cauda).	Site of sperm maturation and storage. Common site for inflammation (epididymitis) and cysts.
Head (Caput)	Superior part, receives sperm from efferent ductules. Widest part.	Composed of convoluted efferent ductules and the initial segment of the epididymal duct.
Body (Corpus)	Lies along the posterolateral margin of the testis.	Main segment for sperm maturation.
Tail (Cauda)	Inferior part, continuous with the vas deferens.	Primary site for sperm storage.
Blood Supply	Testicular Artery (from aorta). Veins form the pampiniform plexus (drains into testicular vein; right to IVC, left to left renal vein).	Pampiniform plexus is important for thermoregulation; varicocele is dilatation of these veins. Testicular torsion involves twisting of the spermatic cord.
Lymphatics	Drain primarily to para-aortic (retroperitoneal) lymph nodes.	Pattern of lymphatic spread is crucial for staging testicular cancers. Scrotal skin drains to inguinal nodes.
Innervation	Autonomic nerves from the renal and aortic plexuses.

Structure	Epithelium & Cell Types	Stroma & Other Features	Key Functions / Notes
Seminiferous Tubules	Complex stratified epithelium: - Spermatogenic Cells: Various stages of development (spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids, spermatozoa). - Sertoli Cells: Large, columnar supporting cells with irregular nuclei, prominent nucleoli, pale cytoplasm, extend from basement membrane to lumen.	- Surrounded by a basement membrane and peritubular myoid cells. - Lumen (post-puberty) contains spermatozoa.	Spermatogenesis (spermatogenic cells). Support, nourishment, phagocytosis, blood-testis barrier, hormone production (inhibin, AMH) (Sertoli cells). Charcot-Böttcher crystalloids can be seen in Sertoli cells.
Interstitial Tissue (between tubules)	- Leydig Cells: Polygonal cells, often in clusters, with abundant eosinophilic granular cytoplasm (may contain lipid droplets, Reinke crystals - pathognomonic but not always seen). - Fibroblasts, macrophages, mast cells, vessels, nerves.	Loose connective tissue with rich vascular supply.	Testosterone production (Leydig cells). Reinke crystals are elongated, rod-shaped cytoplasmic inclusions.
Tubuli Recti (Straight Tubules)	Simple cuboidal to low columnar epithelium (initially Sertoli-like cells, then cuboidal).	Connect seminiferous tubules to rete testis.	Sperm passage.
Rete Testis	Interconnecting channels lined by simple cuboidal to low columnar epithelium, sometimes ciliated.	Located in dense connective tissue of mediastinum testis.	Sperm mixing and transport to efferent ductules.
Efferent Ductules	Alternating groups of tall ciliated columnar cells and shorter non-ciliated cuboidal cells (creating a "scalloped" or "star-shaped" lumen).	Thin layer of smooth muscle.	Fluid resorption and sperm transport from rete testis to epididymis.
Epididymal Duct (Head, Body, Tail)	Pseudostratified columnar epithelium with principal cells (tall columnar with long stereocilia - non-motile microvilli) and basal cells. Stereocilia become shorter towards the tail.	Surrounded by a basement membrane and layers of smooth muscle (muscle layer thickness increases from head to tail).	Sperm maturation (acquisition of motility, fertilizing capacity), sperm concentration (fluid resorption), and sperm storage (especially in tail).
Tunica Albuginea	N/A (Connective tissue)	Dense collagenous connective tissue.	Protective capsule.
Tunica Vaginalis	Simple squamous epithelium (mesothelium).	Thin layer of underlying connective tissue.	Allows testis to move freely within scrotum; serous fluid production.

Kidney

Non-Neoplastic

Xanthogranulomatous Pyelonephritis (XGP)

Chronic destructive granulomatous inflammation of renal parenchyma, often associated with obstruction and infection, characterized by lipid-laden macrophages
Clinical
─ Adults, F>M; associated with recurrent UTIs, nephrolithiasis (esp staghorn calculi), obstruction (e.g., Proteus, E. coli infections)
─ May present with flank pain, fever, malaise, weight loss, palpable mass; can mimic renal malignancy
─ Kidney often non-functional; nephrectomy is usual treatment
Macro
─ Enlarged kidney; renal parenchyma replaced by yellowish, soft, necrotic, or indurated tissue
─ Often associated with staghorn calculi in dilated renal pelvis and calyces; abscess formation common
─ May extend into perinephric fat or adjacent organs
Micro
─ Diffuse infiltrate of foamy (lipid-laden) macrophages (xanthoma cells), neutrophils, lymphocytes, plasma cells, and multinucleated giant cells
─ Granulation tissue, fibrosis, and abscess formation are common
─ Destruction of normal renal parenchyma; cholesterol clefts may be present
─ Michaelis-Gutmann bodies are absent (unlike malakoplakia)
Ancillary studies
─ IHC: Macrophages CD68+
─ Special stains for organisms usually negative (though bacterial infection is underlying cause)
DDx
─ Clear cell RCC (Malignant clear cells, CAIX+, CD10+; lacks extensive inflammation of XGP)
─ Malakoplakia of kidney (Presence of Michaelis-Gutmann bodies, different macrophage appearance)
─ Other granulomatous conditions (e.g., tuberculosis - caseating granulomas, AFB+)
Note
─ A severe form of chronic pyelonephritis resulting in renal destruction
─ Grossly can be mistaken for renal cell carcinoma ("tumor-like" XGP)
Media ─ placeholder ─ Xanthogranulomatous pyelonephritis H&E ─ Xanthogranulomatous pyelonephritis WSI WSI ─ Xanthogranulomatous pyelonephritis (XPN) H&E

Clear Cell RCC

Malignant epithelial tumor composed of cells with clear cytoplasm, part of spectrum of tumors with VHL gene inactivation

Clinical
─ Peak 6th-7th decades, M>F; risk factors include smoking, obesity, hypertension
─ Also associated with acquired cystic disease, chronic hemodialysis, VHL syndrome
─ Often incidental finding; classic triad (hematuria, flank pain, palpable mass) <10% cases
─ Prognosis is stage-dependent; also grade, necrosis, sarcomatoid change are important
Macro
─ Typically golden-yellow cut surface due to lipid; areas of necrosis, fibrosis, cystic change, hemorrhage common
─ May be well circumscribed but usually unencapsulated; larger tumors (>7cm) often involve renal sinus veins/fat
Micro
─ Usually well-circumscribed, often unencapsulated; growth patterns include nests, solid alveoli, tubules, micro/macrocysts, solid sheets with intricate, branching fibrovascular septations; variable cellularity
─ Polygonal clear cells (abundant intracytoplasmic glycogen and lipid), areas with granular/eosinophilic cytoplasm usually higher grade; optically clear or eosinophilic/granular cytoplasm; N:C ratio variable with grade
─ Nuclear features per Fuhrman/WHO-ISUP nucleolar grading (Grade 1: Inconspicuous/absent nucleoli at 400x; Grade 2: Conspicuous/eosinophilic nucleoli at 400x, visible but not prominent at 100x; Grade 3: Conspicuous/eosinophilic nucleoli at 100x; Grade 4: Extreme nuclear pleomorphism, tumor giant cells, rhabdoid/sarcomatoid features)
Ancillary studies
─ IHC (+): PAX8, PAX2, CAIX (Diffuse membranous, box-like), CD10, Vimentin, EMA/MUC1, CK-PAN (AE1/AE3), RCC antigen
─ IHC (-): CK7 (Mostly, or focal in cystic/HG areas), AMACR (Mostly), CD117, Ksp-cadherin, p63, GATA3
─ Molecular: VHL gene mutations (3p25-26) or chromosome 3p losses (>90% sporadic, all VHL syndrome); PBRM1, SETD2, BAP1 mutations also frequent
DDx
─ Multilocular cystic renal neoplasm of LMP (Entirely cystic, no expansile solid nodules, low grade nuclei)
─ Clear cell papillary RCC (Linear nuclear arrangement away from basement membrane, CK7 diffuse+, CAIX cup-shaped+, AMACR-)
─ MiTF/TFE family translocation RCC (Papillary architecture, voluminous clear/eosinophilic cytoplasm, TFE3/TFEB nuclear+)
─ Adrenal cortical tumors (Bubbly cytoplasm, inhibin+, MelanA+)
─ Epithelioid angiomyolipoma (HMB45+, MelanA+)
─ Chromophobe RCC (Eosinophilic variant may have clear cells but usually has perinuclear halos, raisinoid nuclei, CD117+)
Note
─ Most common type of RCC
─ WHO/ISUP nucleolar grading recommended over Fuhrman
Media ─ placeholder ─ Clear cell renal cell carcinoma H&E ─ Clear cell renal cell carcinoma H&E ─ Clear cell renal cell carcinoma H&E ─ Clear cell renal cell carcinoma H&E ─ Clear cell renal cell carcinoma WSI ─ clear cell renal cell carcinoma H&E ─ Cystic/multicystic clear cell renal carcinoma H&E

Multilocular Cystic Renal Neoplasm of Low Malignant Potential

Renal cortical neoplasm composed of numerous clear cell-lined cysts with small clusters of clear cells in tumor septa, no solid expansile masses

Clinical
─ Arises in renal cortex; wide age range (mean 50s), M>F
─ Often incidental; no recurrences or metastases described on mean follow-up >6,5 years; >80% pT1
Macro
─ Well circumscribed, almost always with fibrous pseudocapsule; multicystic cut surface
─ Cysts vary in size, contain serous/bloody fluid; septations thin, no solid/expansile masses
Micro
─ Well circumscribed with fibrous pseudocapsule; multilocular cysts with thin fibrous septa containing low cellularity
─ Cysts lined by cuboidal to flattened clear cells; nuclei are Fuhrman/WHO-ISUP grade 1 or 2 and randomly distributed; cytoplasm is clear with a low N:C ratio
Ancillary studies
─ IHC (+): CK7, CA9 (Box-like pattern), HMWCK (Often); CD10 (Focally luminal)
─ IHC (-): AMACR
─ Molecular: VHL alterations similar to clear cell RCC
DDx
─ Cystic clear cell RCC with regression (Fibrosis, hyalinization, calcification suggesting regression)
─ Cystic clear cell papillary RCC (Linear nuclear arrangement, CAIX cup-shaped)
─ Cystic nephroma (No clear cell nests in septa, ER/PR+ ovarian-type stroma)
─ Cystic partially differentiated nephroblastoma (Pediatric, blastemal elements in septa)
─ Benign multiloculated renal cortical cysts (No clear cell nests in septa)

Renal Papillary Adenoma

Benign epithelial proliferation with papillary, tubular, or tubulopapillary configuration; ≤15 mm by current WHO definition

Clinical
─ Incidental finding; increases with age; higher incidence in chronic renal disease/acquired cystic disease
─ Esp with papillary RCC in same kidney; benign course
Macro
─ Well-circumscribed, grayish-white to yellow nodules; ≤15 mm, unencapsulated
Micro
─ Well circumscribed, unencapsulated; papillary, tubular, or tubulopapillary growth with variable cellularity
─ Cuboidal cells with scant cytoplasm; nuclei are low grade (WHO/ISUP grade 1 or 2) with inconspicuous nucleoli and may show grooves
─ Cytoplasm is scant, amphophilic/basophilic, rarely eosinophilic or clear (not optically transparent but finely granular); high N:C ratio
Ancillary studies
─ IHC (+): CK7, AMACR; CD10 (Often luminal/inverted cup-like)
─ IHC (-):
─ Molecular: Trisomy 7 and 17, loss of Y chromosome (similar to type 1 papillary RCC)
DDx
─ Papillary RCC (Size >15 mm or presence of capsule or high-grade nuclei)
─ Metanephric adenoma (Small primitive blue cells, WT1+, CD57+, often BRAF V600E+)
Note
─ Size criterion changed from ≤5 mm to ≤15 mm in WHO 2016/2022
─ Considered putative precursor of type 1 papillary RCC
Media ─ placeholder ─

Papillary RCC

Malignant epithelial tumor characterized by papillary or tubulopapillary architecture

Clinical
─ Peak 6th-7th decades, M>F; second most common RCC subtype
─ Associated with hereditary papillary renal cancer (HPRC) syndrome (MET mutation); and end-stage renal disease
─ Prognosis generally better than clear cell RCC for same stage; type 1 better than type 2
Macro
─ Often well-circumscribed, frequently with fibrous pseudocapsule; variegated cut surface (tan, yellow, red-brown)
─ Hemorrhage/hemosiderin/foamy macrophages contribute to color; necrosis, hemorrhage, cystic change common
Micro
─ Often encapsulated; papillary, tubulopapillary, tubular, or solid growth with papillae having fibrovascular cores; variable cellularity
─ Cuboidal to columnar cells; Type 1: Small cells with scant amphophilic/basophilic cytoplasm in a single layer on papillae; Type 2: Larger cells with abundant eosinophilic cytoplasm, pseudostratification, and higher nuclear grade; foamy macrophages in papillary cores common (esp Type 1); psammoma bodies and hemosiderin deposition may be present
─ Nuclei per WHO/ISUP nucleolar grade; Type 1 usually low grade, Type 2 often higher grade
─ Cytoplasm is scant and amphophilic/basophilic in Type 1; abundant and eosinophilic in Type 2; N:C ratio is variable
Ancillary studies
─ IHC (+): CK7 (Diffuse, esp Type 1), AMACR (Diffuse granular), CD10 (Often luminal), PAX8, PAX2, RCC antigen
─ IHC (-): CAIX (Mostly, or focal at papillary tips/perinecrotic areas)
─ Molecular: Trisomy 7 and 17, loss of Y chromosome (most common); MET oncogene activating mutations (HPRC and ~13% sporadic type 1)
DDx
─ Clear cell RCC with papillary features (CAIX diffuse box-like+, CK7-, AMACR-)
─ Collecting duct carcinoma (Widely infiltrative, desmoplastic stroma, HMWCK+)
─ MiTF/TFE family translocation RCC (Younger patients, voluminous clear/eosinophilic cells, TFE3/TFEB nuclear+)
─ HLRCC-associated RCC (Prominent nucleoli with perinucleolar halos, FH loss, 2SC+)
─ Clear cell papillary RCC (Linear nuclear arrangement, CAIX cup-shaped+, AMACR-)
─ Metanephric adenoma (Small primitive blue cells, WT1+, CD57+)
─ Papillary adenoma (≤15mm, unencapsulated, low grade)
Note
─ WHO classification into Type 1 and Type 2 based on cytology and architecture; oncocytic variant also recognized
Media ─ placeholder ─ Incidental papillary RCC type 2 H&E ─ Metastatic papillary renal cell carcinoma WSI ─ Papillary RCC H&E ─ Papillary renal cell carcinoma H&E ─ Papillary renal cell carcinoma H&E ─ Papillary renal cell carcinoma H&E ─ Papillary renal cell carcinoma H&E ─ Papillary renal cell carcinoma H&E ─ Papillary renal cell carcinoma H&E ─ Papillary renal cell carcinoma WSI ─ Papillary renal cell carcinoma (Type2) H&E ─ Papillary renal cell carcinoma (pT1) H&E ─ Papillary renal cell carcinoma Type B (columnar cell type) H&E ─ papillary renal cell carcinoma H&E

Collecting Duct Carcinoma

Rare, aggressive malignant epithelial neoplasm arising from epithelium of collecting ducts in renal medulla

Clinical
─ Arises in renal medulla; wide age range (mean 50s-60s), slight M predominance
─ Hematuria, flank pain, palpable mass common; distant metastases at presentation common; poor prognosis
Macro
─ Firm, gray-white, infiltrative mass often centrally located; frequently with necrosis and hemorrhage
─ May involve renal pelvis
Micro
─ Infiltrative with poorly defined borders; growth patterns include tubules, glands, cords, nests, and papillary structures embedded in prominent desmoplastic stroma; often with high-grade dysplasia in adjacent collecting ducts
─ Variable cellularity, often admixed with prominent inflammatory infiltrate (neutrophils, lymphocytes); atypical epithelial cells are cuboidal to columnar and often highly pleomorphic
─ Nuclei are high grade (WHO/ISUP grade 3 or 4) with pleomorphism, prominent nucleoli, and frequent mitoses
─ Cytoplasm is eosinophilic to amphophilic, sometimes vacuolated; high N:C ratio
Ancillary studies
─ IHC (+): PAX8, HMWCK (34βE12), CK7 (Variable), EMA, UEA-1, p63 (Some), GATA3 (Some)
─ IHC (-): CD10, AMACR, CAIX, RCC antigen, Vimentin (Usually)
─ Molecular: Complex chromosomal abnormalities, SMARCB1/INI1 intact (important for DDx with medullary RCC)
DDx
─ Renal medullary carcinoma (Sickle cell trait/disease, SMARCB1/INI1 loss, reticular/yolk sac-like patterns)
─ Urothelial carcinoma of renal pelvis invading kidney (Urothelial CIS, GATA3+, p63+)
─ Papillary RCC, type 2 (Less desmoplasia, lacks HMWCK, often CK7+, AMACR+)
─ High-grade clear cell RCC with sarcomatoid change (CAIX+, CD10+)
─ Metastatic adenocarcinoma (Clinical history, site-specific markers e.g. TTF-1 for lung, CDX2 for colon)
Note
─ Diagnosis of exclusion; aggressive tumor with poor response to conventional RCC therapies
Media ─ placeholder ─ Collecting duct carcinoma H&E ─ Collecting duct carcinoma, Fuhrman grade IV H&E

Chromophobe Renal Cell Carcinoma

Malignant renal epithelial neoplasm thought to arise from intercalated cells of collecting ducts, characterized by cells with pale eosinophilic cytoplasm, perinuclear halos, and "raisinoid" nuclei
Clinical
─ Adults (mean age 50-60s), M=F or slight M predominance
─ Generally good prognosis, better than clear cell or papillary RCC of similar stage; sarcomatoid change worsens prognosis
─ May be associated with Birt-Hogg-Dubé syndrome (often bilateral, multifocal, hybrid oncocytic/chromophobe tumors)
Macro
─ Well-circumscribed, solid, tan-beige to light brown (not typically golden-yellow like ccRCC)
─ Central scar or necrosis may be present in larger tumors
Micro
─ Solid, alveolar, or nested growth patterns; cells are large, polygonal, with distinct cell membranes
─ Cytoplasm: Abundant, pale eosinophilic, flocculent, or finely reticular; characteristic perinuclear clearing (halo) is common
─ Nuclei: Often irregular, "raisinoid" (wrinkled nuclear membranes), hyperchromatic, binucleation common; nucleoli may be visible but not typically prominent like high-grade ccRCC or papillary RCC
─ Two main cell types:
─ Classic (plant-like): Large cells, prominent cell borders, pale cytoplasm, perinuclear halos
─ Eosinophilic variant: Predominance of cells with granular eosinophilic cytoplasm, less prominent halos; can mimic oncocytoma
─ Vascular network is less prominent than in ccRCC
Ancillary studies
─ IHC (+): CK7 (diffuse, strong membranous/cytoplasmic), CD117/KIT (membranous, often strong), PAX8, EMA, E-cadherin
─ IHC (+): Hale's colloidal iron (diffuse, strong cytoplasmic staining - highlights acid mucopolysaccharides)
─ IHC (-): CAIX (usually), CD10 (usually), AMACR, RCC antigen, Vimentin (typically negative or focal)
─ Molecular: Multiple chromosomal losses (hypodiploidy), esp -1, -2, -6, -10, -13, -17, -21; TP53 and PTEN mutations in a subset, esp with sarcomatoid change
DDx
─ Oncocytoma (CK7 typically negative or focal, CD117+, S100A1+, Hale's colloidal iron variable/granular)
─ Clear cell RCC, eosinophilic variant (CAIX+, CD10+, CK7 often-, lacks diffuse Hale's colloidal iron)
─ Papillary RCC, type 2 (Papillary architecture, AMACR+, CK7+)
─ SDH-deficient RCC (SDHB loss, vacuolated cytoplasm)
Note
─ Sarcomatoid differentiation can occur and confers a worse prognosis
─ Distinguishing eosinophilic variant from oncocytoma can be challenging, relies on CK7 and Hale's colloidal iron pattern
Media ─ placeholder ─ Chromophobe H&E ─ Chromophobe renal carcinoma H&E ─ Chromophobe renal cell carcinoma H&E ─ Chromophobe renal cell carcinoma H&E ─ Chromophobe renal cell carcinoma H&E ─ Chromophobe renal cell carcinoma H&E ─ Chromophobe renal cell carcinoma H&E ─ Chromophobe renal cell carcinoma G2, pT2 H&E ─ Chromophobe renal cell carcinoma, Stage pT2, Nx, Mx H&E ─ Renal Cell Carcinoma - Chromophobe type H&E ─ Renal cell carcinoma - Chromophobe H&E CK07 ─ Renal cell carcinoma - Chromophobe H&E

Medullary RCC

Rare, highly aggressive carcinoma arising in renal medulla, almost exclusively in individuals with sickle cell trait or rarely sickle cell disease

Clinical
─ Arises in renal medulla; young patients (mean 20s-30s), African descent common
─ Hematuria, flank pain, weight loss; often advanced stage at diagnosis; extremely poor prognosis
Macro
─ Infiltrative, firm, tan-gray mass in renal medulla; often with hemorrhage and necrosis
─ May invade renal pelvis and perinephric tissues
Micro
─ Highly infiltrative; growth patterns include reticular, cribriform, glandular, solid sheets, and yolk sac tumor-like patterns with prominent desmoplastic stroma and often a prominent neutrophilic infiltrate
─ Variable cellularity with often loosely cohesive, poorly differentiated epithelial cells; cell shapes are pleomorphic, epithelioid, or rhabdoid
─ Nuclei are high grade (WHO/ISUP grade 3 or 4) with vesicular appearance, prominent nucleoli, and frequent mitoses
─ Cytoplasm is eosinophilic, sometimes clear or vacuolated; high N:C ratio
Ancillary studies
─ IHC (+): PAX8 (Often weak/focal), CK7 (Variable), EMA, OCT3/4 (Often)
─ IHC (-): SMARCB1/INI1 (Loss of nuclear expression is characteristic), CAIX, CD10, AMACR, GATA3, p63, SALL4 (Usually)
─ Molecular: SMARCB1 gene inactivation (biallelic)
DDx
─ Collecting duct carcinoma (SMARCB1/INI1 retained, no sickle cell trait, different IHC profile)
─ High-grade urothelial carcinoma (GATA3+, p63+, SMARCB1/INI1 retained)
─ Metastatic carcinoma (Clinical history, site-specific markers)
─ Yolk sac tumor (Rare in kidney, SALL4+, AFP+)
Note
─ Strong association with sickle cell trait is a key diagnostic feature
─ Loss of SMARCB1/INI1 is defining molecular alteration
Media ─ placeholder ─ Renal medullary carcinoma H&E

Oncocytoma of the Kidney

Benign epithelial renal tumor composed of oncocytes (large eosinophilic cells packed with mitochondria)

Clinical
─ Peak 7th decade, M>F (2:1); often incidental discovery
─ Usually sporadic; rare association with Birt-Hogg-Dubé syndrome or tuberous sclerosis complex
─ Excellent prognosis; metastasis is exceptionally rare
Macro
─ Well-circumscribed, mahogany brown or tan; often with central fibrous scar (stellate or linear)
─ Hemorrhage or necrosis uncommon
Micro
─ Well-circumscribed, often with pseudocapsule; growth in solid nests, alveoli, tubules, microcysts; stroma edematous or hyalinized
─ Densely cellular with polygonal oncocytes – large cells with abundant, granular eosinophilic cytoplasm
─ Nuclei round, uniform, centrally located; nucleoli often prominent (Fuhrman/WHO-ISUP grade 2 equivalent); binucleation common
─ "Oncocytic pleomorphism" (degenerative atypia) can be present but not prognostically significant if mitoses absent
─ Cytoplasm abundant, intensely eosinophilic, granular (due to numerous mitochondria); distinct cell borders; low N:C ratio
Ancillary studies
─ IHC (+): S100A1 (Diffuse, strong), PAX8; EMA (Variable); CD117/KIT (Membranous/cytoplasmic, often diffuse); KSP-cadherin (Variable)
─ IHC (+): Hale's colloidal iron (Variable, granular cytoplasmic)
─ IHC (-): CK7 (Typically negative or <5% scattered positive cells); CAIX, AMACR, RCC antigen; Vimentin (Usually negative or focal)
─ Molecular: Loss of chromosomes 1, 14, Y; CCND1 rearrangements; mitochondrial DNA mutations; lacks VHL, 3p, 7, 17 alterations
DDx
─ Chromophobe RCC, eosinophilic variant (Perinuclear halos, "raisinoid" nuclei, diffuse CK7+, diffuse Hale's colloidal iron+)
─ Clear cell RCC, eosinophilic variant (CAIX+, CD10+, often CK7-)
─ Papillary RCC, type 2 (Papillary architecture, CK7+, AMACR+)
─ SDH-deficient RCC (Vacuolated cytoplasm, SDHB loss, 2SC+)
─ Eosinophilic solid and cystic RCC (ESC-RCC) (Solid and cystic areas, chunky cytoplasm, CK20+)
Note
─ Most common benign solid renal epithelial tumor
─ "Oncocytic pleomorphism" should not be overinterpreted as malignancy

Clear cell papillary renal cell tumor

Indolent renal cortical epithelial tumor with (1) clear cells, (2) papillary and/or tubular architecture, and (3) characteristic linear nuclear arrangement away from basement membrane

Clinical
─ Often incidental finding; wide age range (mean 50-60s), slight M>F
─ May be multiple or bilateral, esp in end-stage renal disease; excellent prognosis, no metastases reported
Macro
─ Typically small, well-circumscribed, grayish-white to yellow cortical mass; often cystic
Micro
─ Well-circumscribed, often encapsulated; growth patterns include papillary, tubular, acinar, cystic, and solid sheets; low cellularity
─ Cells are cuboidal to low columnar with clear cytoplasm; nuclei are characteristically arranged in a linear fashion away from the basement membrane (apical/subapical)
─ Nuclei are round to oval, small, uniform (WHO/ISUP grade 1 or 2); nucleoli inconspicuous or absent; mitoses rare
─ Cytoplasm is clear to faintly eosinophilic; N:C ratio low to moderate
Ancillary studies
─ IHC (+): CK7 (Diffuse, strong membranous), CAIX (Cup-shaped/membranous, typically along luminal border or basolateral, not diffuse box-like), PAX8, EMA
─ IHC (-): CD10 (Usually negative or focal), AMACR/P504S (Usually negative), RCC antigen, TFE3, TFEB
─ Molecular: Lacks VHL gene mutations and 3p loss; lacks trisomy 7/17
DDx
─ Clear cell RCC (CAIX diffuse box-like+, CK7 often-, VHL alterations)
─ Papillary RCC (CK7+, AMACR+, CAIX often-, trisomy 7/17)
─ MiTF family translocation RCC (TFE3/TFEB+, often younger patients)
─ Multilocular cystic renal neoplasm of LMP (Entirely cystic, no solid expansile nodules with this specific linear nuclear pattern)
Note
─ Considered a distinct entity with indolent behavior
Media ─ placeholder ─ Clear cell papillary carcinoma H&E ─ Clear cell papillary renal carcinoma H&E ─ Clear cell papillary renal cell carcinoma H&E

Mucinous Tubular and Spindle Cell Carcinoma

Low-grade malignant renal epithelial neoplasm composed of (1) small tubules and (2) spindle cells, embedded in (3) myxoid/mucinous stroma

Clinical
─ Predominantly adult females (F:M ~4:1), wide age range (mean 50s)
─ Often incidental; generally indolent, but rare metastases reported, esp with high-grade features/necrosis
Macro
─ Well-circumscribed, unencapsulated, pale gray or tan-yellow, glistening, myxoid cut surface
─ May show cystic change or hemorrhage
Micro
─ Well-circumscribed; biphasic pattern of tubules/cords and spindle cells in a mucinous/myxoid stroma; low to moderate cellularity
─ Tubules lined by cuboidal cells with scant, pale eosinophilic cytoplasm; spindle cells form fascicles or grow haphazardly
─ Nuclei are small, oval to spindle-shaped, uniform (WHO/ISUP grade 1 or 2); nucleoli inconspicuous; mitoses rare
─ Cytoplasm is scant, pale eosinophilic to amphophilic; N:C ratio moderate to high in spindle cells
Ancillary studies
─ IHC (+): PAX8, AMACR/P504S (Often strong, diffuse), CK7 (Variable, often positive), EMA; Vimentin (Spindle cells)
─ IHC (-): CD10 (Usually), CAIX (Usually), HMWCK, TFE3
─ Molecular: Multiple chromosomal losses, esp -1, -4, -8, -9, -13, -14, -15, -22; monosomy 7 and 17 rare
DDx
─ Papillary RCC with spindle cells (AMACR+, CK7+ but usually more papillary, lacks prominent mucin)
─ Sarcomatoid RCC (High-grade features, necrosis, atypical mitoses, often associated with other RCC subtypes)
─ Metanephric adenofibroma (Lacks significant atypia, WT1+ in stromal component)
─ Angiomyolipoma, epithelioid or spindle cell variant (HMB45+, Melan-A+)
─ Leiomyosarcoma (Smooth muscle markers+, PAX8-)
Note
─ Rare tumor; neuroendocrine differentiation or rhabdoid features may occur
Media ─ placeholder ─ Mucinous tubular and spindle cell carcinoma, pT1 H&E ─ mucinous tubular and spindle cell carcinoma (MTSCC) H&E

Tubulocystic RCC

Rare renal cortical epithelial neoplasm composed of variably sized tubules and cysts lined by eosinophilic cells with prominent nucleoli

Clinical
─ Predominantly adult males (M:F ~7:1), wide age range (mean 50s-60s)
─ Often incidental; generally indolent, but can recur or metastasize, esp if large or with sarcomatoid change
Macro
─ Well-circumscribed, often encapsulated, spongy or "bubble-wrap" appearance due to multiple cysts
─ Cysts contain clear or pale fluid; tan-white to gray solid areas
Micro
─ Well-circumscribed; characteristic pattern of variably sized, closely packed tubules and cysts separated by thin fibrous septa
─ Lined by a single layer of cuboidal to flattened, or hobnail cells with eosinophilic cytoplasm
─ Nuclei are large, round to oval, often with prominent eosinophilic nucleoli (WHO/ISUP grade 3 by definition); mitoses rare
─ Cytoplasm is moderate to abundant, eosinophilic, sometimes granular or clear; N:C ratio moderate
Ancillary studies
─ IHC (+): PAX8, AMACR/P504S (Strong, diffuse), CD10 (Often diffuse), CK7 (Variable, often positive)
─ IHC (-): CAIX (Usually negative or focal), HMWCK, TFE3
─ Molecular: Gains of chromosomes 7 and 17 reported in some cases; some show molecular overlap with papillary RCC
DDx
─ Collecting duct carcinoma (Infiltrative, desmoplastic stroma, HMWCK+)
─ Multilocular cystic renal neoplasm of LMP (Clear cells, lower grade nuclei, CAIX+)
─ Papillary RCC, cystic variant (More complex papillae, different cytology)
─ Acquired cystic disease-associated RCC (Often prominent oxalate crystals, eosinophilic cytoplasm but different architecture)
─ Mixed epithelial and stromal tumor (MEST) (Biphasic, ovarian-type stroma often ER/PR+)
Note
─ Previously considered part of collecting duct carcinoma spectrum by some
Media ─ placeholder ─

Acquired Cystic Disease (ACD) Associated RCC

Renal cell carcinoma arising in the background of acquired cystic disease, typically in patients with end-stage renal disease

Clinical
─ Patients with long-term dialysis or end-stage renal disease; M>F
─ Often multiple and bilateral; prognosis variable, depends on subtype and grade
Macro
─ Tumors arise within kidneys showing multiple cysts of ACD; may be solid or cystic
─ Cut surface appearance depends on RCC subtype (e.g., clear cell, papillary)
Micro
─ Background of ACD: Multiple cysts, often lined by hyperplastic epithelium, with intraluminal calcium oxalate crystals
─ RCC histology varies; most common is similar to clear cell RCC or papillary RCC; a characteristic pattern shows eosinophilic cells with abundant cytoplasm and prominent nucleoli, often with oxalate crystals
─ Sieve-like/cribriform pattern common; foamy macrophages, hemosiderin
Ancillary studies
─ IHC: Depends on the specific RCC subtype; PAX8 generally positive
─ Oxalate crystals are a key feature but not specific
─ Molecular: Variable, may show features of clear cell RCC (3p loss, VHL mut) or papillary RCC (trisomy 7, 17)
DDx
─ Other RCC subtypes not associated with ACD (Clinical history is key)
─ Clear cell papillary RCC (Distinctive linear nuclei, CK7+, CAIX cup-shaped)
─ Multilocular cystic renal neoplasm of LMP (Lacks prominent oxalate, different cell type)
─ Xanthogranulomatous pyelonephritis (Inflammatory, foamy macrophages, but not neoplastic epithelium)
Note
─ Increased risk of RCC development in ACD kidneys; screening often performed
Media ─ placeholder ─ Renal cell carcinoma - Acquired cystic disease associated RCC H&E

Eosinophilic Vacuolated Tumor (EVT) of the Kidney

A relatively recently described renal epithelial neoplasm characterized by solid growth of cells with eosinophilic cytoplasm and prominent intracytoplasmic vacuoles; often associated with mTOR pathway mutations

Clinical

─ Adults, wide age range, slight female predominance reported by some

─ Often incidental finding; generally considered to have indolent behavior or low malignant potential

Macro

─ Well-circumscribed, solid; tan-yellow to brown; variable size

Micro

─ Solid, nested, or sheet-like growth pattern; may have entrapped tubules at periphery; prominent thick-walled blood vessels often seen

─ Cells are large, polygonal, with abundant eosinophilic, granular cytoplasm

─ Characteristic feature: Multiple, variably sized, clear intracytoplasmic vacuoles (lipid or glycogen not always demonstrable)

─ Nuclei are round to oval, often with prominent eosinophilic nucleoli (can appear WHO/ISUP grade 2 or 3)

─ Mitotic activity usually low; necrosis rare

Ancillary studies

─ IHC (+): PAX8, Cytokeratins (e.g., CAM5.2, AE1/AE3); Cathepsin K (often strong); CD117/KIT (variable, can be +); Cyclin D1 (variable)

─ IHC (-): CK7 (usually negative or very focal), CK20, CAIX, AMACR, HMB45, Melan-A, TFE3, SDHB

─ Molecular: Mutations in mTOR pathway genes (TSC1, TSC2, MTOR) are common

DDx

─ Oncocytoma (Lacks prominent vacuoles, S100A1+, usually CK7-)

─ Chromophobe RCC, eosinophilic variant (Perinuclear halos, raisinoid nuclei, CK7 diffuse+, lacks prominent vacuoles)

─ SDH-deficient RCC (Flocculent cytoplasm, may have vacuoles, SDHB loss)

─ Epithelioid angiomyolipoma (HMB45+, Melan-A+)

─ Eosinophilic solid and cystic RCC (ESC RCC) (More prominent cystic component, chunky cytoplasm with basophilic stippling, CK20+)

Note

─ Considered part of the spectrum of "other oncocytic tumors" of the kidney

─ mTOR pathway alterations are a key molecular feature

Media ─ placeholder ─ Renal cell carcinoma - Acquired cystic disease associated RCC H&E

Eosinophilic solid and cystic RCC (ESC-RCC)

Rare renal epithelial neoplasm characterized by solid and cystic architecture, and cells with voluminous eosinophilic cytoplasm; strong female predominance

Clinical
─ Almost exclusively in adult females (F:M >10:1), wide age range
─ Often incidental; generally considered indolent, rare reports of aggressive behavior
Macro
─ Well-circumscribed, variably solid and cystic; cut surface tan-yellow to brown
Micro
─ Well-circumscribed, often with a fibrous capsule; admixture of solid sheets, nests, tubules, and macro/microcysts
─ Cells are large, polygonal with abundant, granular, "chunky" or flocculent eosinophilic cytoplasm; distinct cell borders
─ Nuclei are round to oval, often with prominent nucleoli (can be WHO/ISUP grade 2 or 3); coarse chromatin; intracytoplasmic lumina/vacuoles may be seen
─ Stroma can be edematous or hyalinized; lymphocytic aggregates common
Ancillary studies
─ IHC (+): PAX8, CK20 (Often diffuse, dot-like or Golgi pattern is characteristic), EMA; CK7 (Variable, often patchy)
─ IHC (-): CD117 (Usually), S100A1, CAIX, AMACR, HMB45, Melan-A
─ Molecular: TSC gene mutations (TSC1 or TSC2) identified in a subset, suggesting link to tuberous sclerosis complex-associated oncocytic tumors
DDx
─ Oncocytoma (S100A1+, CD117+, CK20-)
─ Chromophobe RCC, eosinophilic variant (CK7 diffuse+, CD117+, perinuclear halos, "raisinoid" nuclei, CK20-)
─ SDH-deficient RCC (SDHB loss, vacuolated cytoplasm)
─ FH-deficient RCC (HLRCC) (Very prominent nucleoli with perinuclear halos, FH loss, 2SC+)
─ Epithelioid angiomyolipoma (HMB45+, Melan-A+)
Note
─ Distinct entity, CK20 positivity is a key feature
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Molecularly Defined RCCs

SDH-Deficient Renal Cell Carcinoma

Renal cortical tumor with SDHB loss by IHC, linked to germline SDHx mutations
Clinical
─ Cortex; younger age (mean 37-40 yrs), M>=F; germline SDHx mutation, Carney-Stratakis syndrome
─ Family hx of paraganglioma, pheochromocytoma, GIST; often incidental, hematuria; variable prognosis, can metastasize
Macro
─ Well-circumscribed; tan-yellow, pink, or red-brown; cystic change, hemorrhage; variable size
Micro
─ Well-circumscribed, capsule; solid, nested, alveolar, tubular; flocculent eosinophilic cytoplasm, intracytoplasmic vacuoles
─ Polygonal cells; typically low grade nuclei (WHO/ISUP G2), inconspicuous nucleoli; high-grade transformation possible
─ Abundant eosinophilic, flocculent cytoplasm; intracytoplasmic lumina common
Ancillary studies
─ IHC (+): PAX8 (often weak/patchy), EMA (variable)
─ IHC (-): SDHB (hallmark loss); CK7 (-/focal), CAIX (-/focal), CD10 (-/focal), AMACR (-/focal), CD117 (-)
─ Molecular: Germline SDHA, SDHB, SDHC, SDHD, or SDHAF2 mutations
DDx
─ Clear cell RCC (CAIX+, CD10+, SDHB+); Papillary RCC (AMACR+, CK7+, SDHB+)
─ Chromophobe RCC (CD117+, CK7 diffuse+, SDHB+); Oncocytoma (CD117+, S100A1+, SDHB+)
─ FH-deficient RCC (FH loss, 2SC+, prominent nucleoli with halos, SDHB+)
Note
─ SDHB IHC loss is surrogate for SDH deficiency; consider in young patients with eosinophilic RCC
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MiT Family Translocation Renal Cell Carcinomas

Xp11 Translocation Renal Cell Carcinoma (TFE3-rearranged RCC)

RCC with TFE3 gene translocations, leading to TFE3 protein overexpression
Clinical
─ children & young adults (median 25-35 yrs), any age; slight F>M or M>F
─ Prior chemotherapy rare risk; typically sporadic; hematuria, pain, mass; often advanced stage
─ Prognosis variable, often aggressive in adults; better in children
Macro
─ Variable; tan-yellow, gray-white, red-brown; hemorrhage, necrosis, cystic change; can be large
Micro
─ Well-circumscribed or infiltrative; papillary, nested, alveolar, sheets; high cellularity
─ Polygonal cells; voluminous clear and/or eosinophilic cytoplasm; high nuclear grade (WHO/ISUP 3-4), prominent nucleoli
─ Psammoma bodies may be present; abundant clear/eosinophilic cytoplasm
Ancillary studies
─ IHC (+): TFE3 (nuclear); PAX8; Cathepsin K (often); CD10 (variable), AMACR (variable), Melan-A (variable), HMB45 (variable)
─ IHC (-): CK7 (usually); EMA (often -/weak); CAIX (often -/weak)
─ Molecular: TFE3 fusions (ASPSCR1, PRCC, SFPQ, CLTC, NONO etc)
DDx
─ Clear cell RCC (TFE3-, CAIX diffuse+); Papillary RCC (TFE3-, AMACR+, CK7+)
─ Chromophobe RCC (TFE3-, CD117+); Epithelioid angiomyolipoma (HMB45+, MelanA+, usually TFE3-)
Note
─ TFE3 break-apart FISH confirmatory; wide morphologic spectrum
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t(6;11) Renal Cell Carcinoma (TFEB-rearranged RCC)

RCC with t(6;11)(p21;q12) translocation (MALAT1-TFEB fusion), TFEB overexpression
Clinical
─ children & young adults (median ~30 yrs); F>M reported
─ Sporadic; hematuria, pain, mass, incidental; can metastasize, sometimes late
─ Prognosis generally more indolent than TFE3 RCC
Macro
─ Well-circumscribed; tan-gray or yellowish; often smaller than TFE3 RCCs
Micro
─ Well-circumscribed; biphasic: larger epithelioid cells & smaller cells around hyaline basement membrane material (colloid-like)
─ Nested or tubular; larger cells clear/eosinophilic cytoplasm, smaller cells darker nuclei
─ Larger cells vesicular nuclei, prominent nucleoli
Ancillary studies
─ IHC (+): TFEB (nuclear); Melan-A (often); HMB45 (often); Cathepsin K (often); PAX8
─ IHC (-): CK7; CD10 (-/focal); AMACR; EMA
─ Molecular: MALAT1-TFEB fusion defining; other rare TFEB fusions
DDx
─ Xp11 translocation RCC (TFEB-, TFE3+); Epithelioid angiomyolipoma (Melanocytic marker+, TFEB-)
─ Clear cell RCC (TFEB-, CAIX+); Chromophobe RCC, eosinophilic (TFEB-, CD117+, CK7+)
Note
─ TFEB break-apart FISH confirmatory; biphasic pattern with basement membrane material characteristic
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Fumarate Hydratase-Deficient Renal Cell Carcinoma (HLRCC-associated RCC)

Aggressive RCC with FH gene inactivation, FH protein loss, 2SC accumulation
Clinical
─ young adults (mean 30s-40s); M=F; HLRCC syndrome (germline FH mutation)
─ Cutaneous/uterine leiomyomas; often asymptomatic or nonspecific; early widespread metastases
─ Highly aggressive, poor prognosis
Macro
─ Variable size; solitary; well-circumscribed or infiltrative; tan-yellow, pink, hemorrhagic; cystic changes common
Micro
─ Variable circumscription; papillary, tubulopapillary, cribriform, solid, cystic; large cells with prominent eosinophilic nucleoli with clear halo
─ High cellularity; polygonal, cuboidal cells; predominantly eosinophilic
─ Hallmark: very large eosinophilic nucleoli with perinuclear halos; high nuclear grade
Ancillary studies
─ IHC (+): 2SC (S-(2-succino)-cysteine) (diffuse nuclear/cytoplasmic); PAX8; CK7 (often +/patchy); AMACR (variable)
─ IHC (-): FH (fumarate hydratase) (complete loss); CAIX (-/focal); CD10 (-/focal); CD117 (-)
─ Molecular: Biallelic FH gene inactivation (1q43)
DDx
─ Papillary RCC, Type 2 (FH+, 2SC-, less prominent nucleolar features)
─ Collecting duct carcinoma (Medullary, desmoplasia, FH+, 2SC-); Tubulocystic RCC (Distinct morphology, FH+, 2SC-)
Note
─ Consider HLRCC syndrome; aggressive management crucial; characteristic nucleoli key
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ELOC (TCEB1)-Mutated Renal Cell Carcinoma

RCC with somatic ELOC (TCEB1) mutations, often resembling ccRCC but distinct
Clinical
─ adults (median 50-60s); M>F reported; sporadic
─ Often incidental; hematuria, flank pain; generally indolent or low malignant potential
Macro
─ Well-circumscribed; tan-yellow or gray-white; often solid
Micro
─ Well-circumscribed, thick fibrous capsule; solid to compact nested; tubules, cysts may be present
─ Prominent thick fibromuscular/collagenous stroma characteristic; predominantly clear cells
─ Nuclei low-intermediate grade (WHO/ISUP G2-3); nuclear stratification/pseudostratification; prominent nucleoli
Ancillary studies
─ IHC (+): CK7 (diffuse strong membranous); CAIX (diffuse membranous, box-like); PAX8
─ IHC (-): CD10 (often -/focal); AMACR; CD117
─ Molecular: Somatic ELOC (TCEB1) mutations
DDx
─ Clear cell RCC (CK7 usually -/focal, lacks prominent fibromuscular stroma)
─ Clear cell papillary RCC (CAIX cup-like, AMACR-, different nuclei)
Note
─ Clear cells + diffuse strong CK7 + CAIX is highly suggestive
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ALK-Rearranged Renal Cell Carcinoma

Rare RCC with ALK gene translocations, ALK protein overexpression
Clinical
─ Kidney, medullary involvement in sickle cell trait; children & young adults, also older
─ M=F or slight M predilection; association with sickle cell trait (esp VCL-ALK)
─ Hematuria, flank pain; can be aggressive, esp with sickle cell trait
Macro
─ Poorly circumscribed, infiltrative; tan-white or hemorrhagic; often involves renal medulla/sinus
Micro
─ Often infiltrative; solid sheets, nests, papillary, cribriform, rhabdoid, spindled; mucinous/myxoid stroma
─ Prominent inflammation; eosinophilic/amphophilic cells; signet ring cells characteristic in some fusions
─ High nuclear grade, pleomorphism, prominent nucleoli, frequent mitoses
Ancillary studies
─ IHC (+): ALK (cytoplasmic/membranous); PAX8 (often); CK7 (variable); EMA (variable); TTF1 (can be +)
─ IHC (-): CAIX; CD10; AMACR
─ Molecular: ALK gene rearrangements (VCL, TPM3, EML4 etc)
DDx
─ Collecting duct carcinoma (ALK-); Renal medullary carcinoma (SMARCB1 loss, ALK-)
─ High-grade urothelial carcinoma (GATA3+, p63+, ALK-)
Note
─ ALK IHC is screen, FISH confirms; VCL-ALK often has signet ring cells, sickle cell trait
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Renal Medullary Carcinoma (SMARCB1-Deficient Medullary Carcinoma)

Aggressive medullary carcinoma in sickle cell trait/disease, SMARCB1 (INI1) loss
Clinical
─ Renal medulla; adolescents & young adults (median 20s-30s); M>F (~2:1)
─ Sickle cell trait (HbAS) almost universal; rarely HbSS or other hemoglobinopathies
─ Gross hematuria, flank pain, mass; advanced stage common; extremely poor prognosis
Macro
─ Poorly circumscribed, infiltrative medullary mass; gray-white or tan; firm; hemorrhage, necrosis
Micro
─ Infiltrative; reticular/sieve-like pattern common (YST-like); solid, adenoid cystic-like, microcystic
─ Prominent desmoplastic stroma; marked neutrophilic infiltrate; poorly differentiated cells, rhabdoid features
─ High-grade nuclei, pleomorphism, prominent nucleoli, mitoses; sickled RBCs in stroma/vessels
Ancillary studies
─ IHC (+): PAX8 (-/weak/patchy); Cytokeratins (variable); EMA; OCT3/4 (focal), SALL4 (variable)
─ IHC (-): SMARCB1 (INI1) (complete nuclear loss - hallmark); GATA3; p63; CD10; CAIX; CK20 (often, per user note)
─ Molecular: Biallelic SMARCB1 (INI1) gene inactivation (22q11.2)
DDx
─ Collecting duct carcinoma (Older, no sickle cell, SMARCB1 intact, HMWCK+)
─ High-grade urothelial carcinoma (GATA3+, p63+, SMARCB1 intact)
─ ALK-rearranged RCC (ALK+, SMARCB1 intact, may be in sickle cell trait)
Note
─ Diagnosis needs clinical correlation (sickle cell) & SMARCB1/INI1 IHC; extremely aggressive
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Metanephric Tumors

Metanephric Adenoma

Benign renal epithelial neoplasm composed of small, uniform, primitive blue cells forming tubules and glomerulus-like structures
Clinical
─ wide age range, 40-50s, also pediatric; F>M (2:1)
─ Often incidental; benign, no metastatic potential
Macro
─ circumscribed, unencapsulated or thinly encapsulated; tan-gray; solid, firm; variable size
Micro
─ Well-circumscribed, unencapsulated; packed small acini, tubules; embryonal appearance
─ Uniform, small, round to oval "blue" cells; scant cytoplasm; indistinct cell borders
─ Nuclei round to oval, hyperchromatic or vesicular, minimal atypia, inconspicuous nucleoli, rare mitoses
─ Stroma scant, paucicellular, may be edematous or hyalinized; psammoma bodies common
Ancillary studies
─ IHC (+): WT1); PAX8; PAX2; CD57 (often); BRAF V600E (protein, if mutated)
─ IHC (-): CK7 (usually); AMACR; EMA (or focal); CD10 (or focal); HMWCK
─ Molecular: BRAF V600E
DDx
─ Papillary RCC, solid variant (CK7+, AMACR+, larger cells, more atypia)
─ Wilms tumor (epithelial predominant) (Younger, blastema, other components)
─ Solid variant of clear cell papillary RCC (CK7+, CAIX cup-like+)
─ Carcinoid tumor
Note
─ Lack of foamy macrophages helps distinguish from some papillary neoplasms
─ Papillary-like structures can be present but are not true fibrovascular cores
Media ─ placeholder ─ Metanephric adenoma H&E ─ Metanephric adenoma H&E ─ Metanephric adenoma H&E ─ Metanephric adenoma H&E ─ Metanephric adenoma H&E ─ Metanephric adenoma H&E ─ Metanephric adenoma WSI

Metanephric Adenofibroma

Essentially a metanephric adenoma with abundant stroma
Clinical
─ wide age range, younger adults/children; F>M
─ Incidental; benign, excellent prognosis
Macro
─ Well-circumscribed; gray-white, firm; may have cystic areas; variable size
Micro
─ Biphasic: epithelial component resembles metanephric adenoma; stromal component is prominent, variably cellular, bland spindle cells
─ Stromal cells are spindle-shaped, bland, may show hyalinization or edema
Ancillary studies
─ Epithelial component: IHC (+) WT1, PAX8, PAX2; IHC (-) CK7
─ Stromal component: IHC (+) CD34 (variable); IHC (-) cytokeratins, S100
─ Molecular: BRAF V600E
DDx
─ Wilms tumor (Blastema, anaplasia, heterologous elements, more aggressive)
─ Mixed epithelial and stromal tumor (MEST) (Ovarian stroma, ER/PR+, lined by hobnail cells)
─ Angiomyolipoma with epithelial cysts (Melanocytic markers in stroma)
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Metanephric Stromal Tumor

Rare benign renal mesenchymal neoplasm composed of bland spindle cells, often with "onion-skinning" around entrapped tubules
Clinical
─ predominantly children and young adults (~2 years); F>M
─ Abdominal mass; benign, excellent prognosis
Macro
─ circumscribed, unencapsulated; tan-white, firm; whorled appearance; variable size
Micro
─ Well-circumscribed; bland spindle cells in fascicles or storiform; low to moderate cellularity
─ concentric "onion-skin" layering of spindle cells around entrapped renal tubules/glomeruli
─ Angiodysplasia (thick-walled, hyalinized vessels); calcification, ossification may occur
─ Spindle cells have scant cytoplasm, oval to elongated nuclei, fine chromatin, inconspicuous nucleoli, rare mitoses
Ancillary studies
─ IHC (+): CD34 (diffuse)
─ IHC (-): Cytokeratins (except entrapped tubules); S100; Desmin; Actin; HMB45; WT1
DDx
─ Congenital mesoblastic nephroma, cellular variant (Infants, infiltrative, more cellular, mitotically active)
─ Solitary fibrous tumor
─ Angiomyolipoma, leiomyoma-like (Melanocytic markers+)
Note
─ Entrapped tubules are benign and part of the lesion, not neoplastic epithelium
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Cystic Nephroma (Multilocular Cystic Nephroma)

Benign, purely cystic renal neoplasm composed of multiple, non-communicating cysts lined by flattened to cuboidal epithelium, with septa containing ovarian-type stroma; considered part of the mixed epithelial and stromal tumor (MEST) family, typically occurring in children and young women.
Clinical
─ Bimodal age distribution: young children (<4 years, M>F) and perimenopausal women (40-60s, F>M); pediatric cases are more common
─ Presents as abdominal mass, pain, or hematuria; incidental finding in some
─ Benign, excellent prognosis after complete excision; no recurrence or metastasis
Macro
─ Well-circumscribed, encapsulated, multiloculated cystic mass; no solid expansile nodules
─ Cysts vary in size, contain clear, serous, or hemorrhagic fluid; septa are fibrous
Micro
─ Exclusively composed of multiple, non-communicating cysts separated by fibrous septa
─ Cysts lined by a single layer of flattened, cuboidal, or hobnail epithelial cells; epithelium is bland, without atypia
─ Septa are composed of paucicellular fibrous tissue or cellular ovarian-type stroma (spindle cells resembling ovarian stroma); ovarian-type stroma is characteristic, esp in adult females
─ No blastemal elements, no clear cell nests, no solid expansile growth within septa (distinguishes from MCRN ديالى LMP and CPDN)
─ Entrapped normal renal elements (glomeruli, tubules) may be seen in septa or at periphery
Ancillary studies
─ Epithelial lining IHC (+): PAX8, CK7 (variable), EMA
─ Ovarian-type stroma IHC (+): ER, PR, CD10 (stromal cells), Inhibin (variable), Calretinin (variable)
─ IHC (-): WT1 (in epithelial component, distinguishes from CPDN blastema), CAIX (distinguishes from MCRN-LMP)
DDx
─ Multilocular cystic renal neoplasm of low malignant potential (MCRN ديالى LMP) (Clear cell nests in septa, CAIX+)
─ Cystic partially differentiated nephroblastoma (CPDN) (Pediatric, blastemal or other nephroblastic elements in septa, WT1+ in blastema)
─ Mixed epithelial and stromal tumor (MEST) (Adults, essentially the adult counterpart; may have more solid stromal areas)
─ Cystic clear cell RCC (Solid expansile nodules of clear cells, cytologic atypia)
─ Benign multilocular renal cortical cysts (Lack ovarian-type stroma or clear cell nests)
Note
─ Pediatric cystic nephroma and adult MEST are closely related, differing mainly by age and relative stromal component
─ Complete excision is curative
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Mixed Epithelial and Stromal Tumor (MEST)

Benign biphasic renal neoplasm composed of cystic/tubular epithelial elements and a prominent ovarian-type stromal component
Clinical
─ Predominantly perimenopausal women (mean age 40-50s), rare in men (often with androgen ablation history)
─ Often incidental; may present with flank pain, hematuria; benign, rare malignant transformation reported
Macro
─ Well-circumscribed, often partially encapsulated; solid and cystic appearance; tan-yellow, gray-white
─ Cysts vary in size, contain serous or hemorrhagic fluid; variable size overall
Micro
─ Biphasic: epithelial component consists of variably sized, non-communicating cysts and tubules; stromal component is cellular, ovarian-like
─ Cysts/tubules lined by flattened, cuboidal, columnar, or hobnail epithelial cells; minimal atypia
─ Stroma is cellular, composed of spindle cells resembling ovarian stroma; may show luteinization or hyalinization; no significant atypia or mitoses
Ancillary studies
─ Epithelial component IHC (+): PAX8, CK7 (variable), EMA
─ Stromal component IHC (+): ER, PR, CD10 (stromal cells), Inhibin (variable), Calretinin (variable), Smooth muscle actin (variable)
─ IHC (-): Cathepsin K (stromal cells usually negative, helps distinguish from AML with epithelial cysts)
─ Molecular: No consistent recurrent alterations identified
DDx
─ Cystic nephroma (Pediatric MEST counterpart, exclusively cystic, no solid areas, younger age)
─ Angiomyolipoma with epithelial cysts (Stromal cells HMB45+, Melan-A+)
─ Adult cystic nephroma (Previously used term, now largely encompassed by MEST)
─ Tubulocystic RCC (Eosinophilic cells, prominent nucleoli, AMACR+)
─ Multilocular cystic renal neoplasm of LMP (Clear cells, CAIX+)
Note
─ Spectrum of tumors including adult cystic nephroma
─ Ovarian-type stroma is a key diagnostic feature
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Renal Mesenchymal Tumors

Renal Hemangioblastoma

Rare benign vascular neoplasm of the kidney, histologically identical to hemangioblastoma of the central nervous system; may be sporadic or associated with von Hippel-Lindau (VHL) syndrome Clinical ─ Adults, wide age range; may be associated with VHL syndrome (patients often younger, may have bilateral/multiple lesions, or other VHL-associated tumors like ccRCC, pheochromocytoma) ─ Often incidental; may cause hematuria, flank pain, or polycythemia (due to erythropoietin production by stromal cells) ─ Benign, excellent prognosis after complete excision Macro ─ Well-circumscribed, often cystic with a mural nodule, or solid; reddish-brown or yellow (due to lipid) ─ Variable size Micro ─ Highly vascular neoplasm composed of two main cell types:

Stromal cells: Polygonal cells with clear, lipid-rich, or eosinophilic cytoplasm; nuclei are round to oval, often bland, but can show pleomorphism (which does not necessarily indicate malignancy)
Capillary network: Numerous thin-walled, small blood vessels (capillaries) forming a rich network between stromal cells ─ Mast cells are often scattered throughout ─ Cystic spaces may be present; hemorrhage or hemosiderin deposition can be seen Ancillary studies ─ Stromal cells IHC (+): Inhibin-alpha (often), Neuron-specific enolase (NSE), S100 protein (variable), PAX2 (variable), D2-40 (podoplanin, variable) ─ Stromal cells IHC (-): Cytokeratins, EMA, CD10, CAIX, RCCma (helps distinguish from ccRCC) ─ Vascular endothelial cells IHC (+): CD31, CD34, Factor VIII-related antigen DDx ─ Clear cell RCC (CAIX+, CD10+, cytokeratin+, inhibin-) ─ Angiomyolipoma (HMB45+, Melan-A+) ─ Metastatic hemangioblastoma from CNS (Clinically indistinguishable from primary renal if VHL context is absent) ─ Vascular malformation (Lacks prominent stromal cell component) Note ─ Presence of renal hemangioblastoma should prompt consideration of VHL syndrome, especially in younger patients or with multiple lesions Media ─ placeholder ─

Angiomyolipoma (AML)

Mesenchymal neoplasm composed of variable admixture of thick-walled dysmorphic blood vessels, spindle cells (smooth muscle-like), and mature adipose tissue; a PEComa
Clinical
─ Adults (mean age 40-50s), F>M; associated with tuberous sclerosis complex (TSC1/TSC2 mutations) in ~20% (often multiple, bilateral)
─ Sporadic cases more common; often incidental, can present with flank pain, hematuria, life-threatening retroperitoneal hemorrhage (Wunderlich syndrome)
─ Prognosis generally benign; epithelioid variant has malignant potential
Macro
─ Well-circumscribed, unencapsulated; tan-yellow, gray, red; variable amounts of fat visible; size varies greatly
Micro
─ Triphasic (classic): 1) Dysmorphic, thick-walled blood vessels (often hyalinized, lacking elastic lamina); 2) Spindled smooth muscle-like cells (often perivascular); 3) Mature adipose tissue
─ Variants: lipoma-like (fat predominant), leiomyoma-like (spindle cell predominant), epithelioid (≥80% epithelioid cells, malignant potential)
─ Spindle cells are plump to elongated, eosinophilic cytoplasm; adipocytes mature; epithelioid cells large, polygonal, eosinophilic/clear cytoplasm, atypical nuclei
Ancillary studies
─ IHC (+): Melanocytic markers (HMB45, Melan-A, MiTF) in spindle/epithelioid cells; Smooth muscle markers (SMA, desmin, calponin) in spindle cells
─ IHC (-): Epithelial markers (CKs, PAX8); S100 (except fat component)
─ Molecular: TSC1 or TSC2 gene mutations in both sporadic and TSC-associated cases
DDx
─ Clear cell RCC (Melanocytic markers-, PAX8+, CAIX+)
─ Sarcomatoid RCC (High-grade, pleomorphic, epithelial markers often +, melanocytic markers-)
─ Liposarcoma (MDM2 amplification, distinct morphology, melanocytic markers-)
─ Leiomyoma (Melanocytic markers-, HMB45-)
Note
─ Epithelioid AML is considered malignant
─ Part of the PEComa (Perivascular Epithelioid Cell tumor) family
Media ─ placeholder ─ Angiomyolipoma (AML) WSI ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma H&E ─ Angiomyolipoma WSI ─ Angiomyolipoma WSI ─ Angiomyolipoma WSI

Epithelioid Angiomyolipoma

Variant of AML composed predominantly (≥80%) of epithelioid cells, considered malignant
Clinical
─ Adults, similar age to classic AML; higher association with TSC than classic AML
─ More aggressive than classic AML; risk of metastasis and death
Macro
─ Often larger, more solid, less obvious fat than classic AML; may show necrosis, hemorrhage
Micro
─ Predominantly sheets of large polygonal epithelioid cells with abundant eosinophilic or clear cytoplasm
─ Nuclei often large, vesicular, with prominent nucleoli; atypia, pleomorphism, mitoses can be prominent
─ Minimal fat, vessels, or spindle cells may be present
Ancillary studies
─ IHC (+): HMB45, Melan-A, MiTF; SMA (variable); Cathepsin K
─ IHC (-): CKs, PAX8, S100 (usually)
DDx
─ Clear cell RCC (HMB45-, Melan-A-, CAIX+, PAX8+)
─ Chromophobe RCC, eosinophilic variant (HMB45-, Melan-A-, CD117+, CK7+)
─ Oncocytoma (HMB45-, Melan-A-, CD117+, S100A1+)
Note
─ Malignant potential correlates with atypia, necrosis, mitotic activity, size
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Juxtaglomerular Cell Tumor

Rare benign mesenchymal neoplasm composed of cells resembling juxtaglomerular cells, produces renin
Clinical
─ Young adults (mean age 20-30s), slight F>M
─ Presents with hypertension (due to hyperreninemia), hypokalemia, headache; surgical excision is curative
Macro
─ Well-circumscribed, encapsulated; small (<5cm); tan-yellow or gray-white; solid
Micro
─ Well-circumscribed, often encapsulated; sheets, nests, or trabeculae of uniform polygonal cells with round to oval nuclei
─ Cells have eosinophilic to clear granular cytoplasm; may form perivascular rosettes or hemangiopericytoma-like pattern
─ Prominent vasculature; entrapped tubules may be present; no significant atypia or mitoses
Ancillary studies
─ IHC (+): Renin (cytoplasmic granular, diagnostic); CD34 (often); Vimentin; SMA (variable)
─ IHC (-): Cytokeratins; S100; HMB45; Chromogranin; Synaptophysin
─ EM: Rhomboid-shaped renin protogranules in cytoplasm
DDx
─ Metanephric adenoma (WT1+, renin-, different morphology)
─ Carcinoid tumor (Neuroendocrine markers+, renin-)
─ Glomus tumor (SMA diffuse+, renin-)
─ Angiomyolipoma (HMB45+, Melan-A+, renin-)
Note
─ Hypertension due to renin secretion is a key clinical feature
─ PASD+ granules may be seen
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Renomedullary Interstitial Cell Tumor (Medullary Fibroma)

Common benign mesenchymal neoplasm of the renal medulla, likely derived from interstitial cells
Clinical
─ Adults, wide age range; M=F; almost always incidental finding at autopsy or nephrectomy
─ Asymptomatic; benign, no malignant potential
Macro
─ Small (<0.5 cm, rarely larger); well-circumscribed, unencapsulated; white-gray, firm; located in renal medulla (pyramids)
Micro
─ Poorly circumscribed at periphery, blends with medulla; bland spindle to stellate cells in a loose, myxoid, or collagenous stroma
─ Entrapped medullary tubules common; cells have scant pale cytoplasm, indistinct borders
─ Nuclei are oval to spindle, bland, with fine chromatin, inconspicuous nucleoli; no mitoses
Ancillary studies
─ IHC (+): Vimentin; Cyclooxygenase-2 (COX-2); Prostaglandin E2 synthase (PGE2)
─ IHC (-): Cytokeratins (except entrapped tubules); S100; CD34; SMA; Desmin; ER; PR
DDx
─ Usually distinctive due to location and morphology in small lesions
─ Larger lesions could consider other spindle cell tumors if atypia present (rare for this entity)
Note
─ Believed to be source of prostaglandins; may have antihypertensive effect
─ Treatment unnecessary if incidentally found and typical
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Embryonal Neoplasms of the Kidney / Nephroblastic Tumors

Nephrogenic Rests

Putative precursor lesions of Wilms tumor; foci of persistent embryonal cells (nephroblastic elements) after 36 weeks gestation
Clinical
─ Found in ~1% of infant kidneys; increased incidence in syndromic Wilms tumor (eg, WAGR, Denys-Drash, Beckwith-Wiedemann)
─ Risk factor for Wilms tumor development; perilobar rests associated with synchronous bilateral Wilms tumors
Macro
─ Usually microscopic; may be visible as pale nodules in cortex (perilobar) or deeper (intralobar)
Micro
─ Foci of embryonal cells resembling stages of nephrogenesis; blastema, tubules, glomerulus-like structures
─ Types: Perilobar (superficial cortex, sharply demarcated, often multiple); Intralobar (deeper cortex/medulla, irregular borders, often solitary, more fibrotic stroma)
─ Subtypes: Nephroblastomatosis (diffuse/multifocal rests); Sclerosing, dormant, hyperplastic, adenomatous, regressing rests
─ Cells are small, blue, with scant cytoplasm, hyperchromatic nuclei
Ancillary studies
─ IHC (+): WT1 (blastema, tubules); PAX2 (blastema, tubules); SIX1/2 (blastema)
─ IHC (-): CK7 (usually negative in blastema)
DDx
─ Wilms tumor (Larger, destructive, often triphasic with stromal component, mitotically active)
─ Metanephric adenoma (BRAF V600E+, older age usually, different morphology)
Note
─ Presence and type of rests can have implications for Wilms tumor risk and prognosis
─ Perilobar rests have lower risk of progressing to Wilms tumor than intralobar rests
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Cystic Partially Differentiated Nephroblastoma (CPDN)

Rare, benign cystic renal neoplasm of childhood, considered a differentiated form of Wilms tumor with excellent prognosis
Clinical
─ Primarily infants and young children (mean age <2 years); M>F
─ Presents as abdominal mass; excellent prognosis, no metastases if criteria strictly met
Macro
─ Well-circumscribed, multiloculated cystic mass; no solid expansile nodules
─ Cysts contain serous or hemorrhagic fluid; septa are fibrous, may be thick
Micro
─ Entirely cystic, multilocular architecture; cysts lined by flattened, cuboidal, or hobnail epithelium
─ Septa contain differentiated nephroblastic elements: blastema (small, focal, non-expansile), immature tubules, glomerulus-like structures; mature spindle cell stroma
─ No expansile solid nodules of blastema; no anaplasia; no rhabdomyogenesis or other heterologous elements
Ancillary studies
─ IHC (epithelial/blastemal components): WT1 (+), PAX2 (+)
DDx
─ Multilocular cystic renal neoplasm of low malignant potential (Adults, clear cells, CAIX+)
─ Wilms tumor, cystic (Expansile solid blastemal nodules present)
─ Mixed epithelial and stromal tumor (MEST) (Adults, ovarian-type stroma, ER/PR+)
Note
─ Diagnosis requires complete sampling to exclude solid Wilms tumor components
─ Considered a benign entity if strict criteria are met
Media ─ placeholder ─ Cystic partially differentiated Wilm's H&E

Nephroblastoma (Wilms Tumor)

Malignant embryonal neoplasm of the kidney composed of variable admixture of blastema, epithelium, and stroma, recapitulating stages of nephrogenesis
Clinical
─ Most common renal malignancy of childhood (peak age 3-4 years); rare in adults
─ Associated syndromes: WAGR, Denys-Drash, Beckwith-Wiedemann, isolated hemihypertrophy
─ Presents as abdominal mass, pain, hematuria, hypertension; prognosis depends on histology (favorable vs anaplastic) and stage
Macro
─ Large, solitary, well-circumscribed but unencapsulated mass; tan-gray, fleshy, variegated
─ Hemorrhage, necrosis, cystic change common; may invade renal vein/sinus
Micro
─ Classic triphasic pattern: 1) Blastema (sheets of small blue cells, high N:C, mitotically active); 2) Epithelium (abortive tubules, glomerulus-like structures); 3) Stroma (undifferentiated spindle cells, may show skeletal muscle, fat, cartilage, bone differentiation)
─ Monophasic or biphasic variants occur; anaplasia (marked nuclear atypia, multipolar mitoses) is key adverse prognostic factor (focal or diffuse)
─ Regressive changes, rhabdomyomatous differentiation, mucinous epithelial differentiation can be seen
Ancillary studies
─ Blastema IHC (+): WT1, PAX2, SIX1/2, CD56
─ Epithelium IHC (+): Cytokeratins, EMA, WT1, PAX2
─ Stroma: Vimentin; specific markers if differentiated (eg, desmin for muscle)
─ Molecular: WT1, CTNNB1, WTX (AMER1), TP53 (in anaplastic), MYCN, SIX1/2 alterations
DDx
─ Nephrogenic rests (Precursor, smaller, no stromal component usually, less atypia)
─ Metanephric adenoma (BRAF V600E+, older age usually, no true blastema)
─ Congenital mesoblastic nephroma (Infants, spindle cell predominant, ETV6-NTRK3 fusion)
─ Clear cell sarcoma of kidney (BCOR alterations, distinct morphology)
─ Rhabdoid tumor of kidney (SMARCB1 loss, distinct morphology)
Note
─ Histology (favorable vs anaplastic) is most important prognostic factor
─ Staging by Children's Oncology Group (COG)
Media ─ placeholder ─ Wilm's tumour H&E

Bladder

Non-Neoplastic

Normal Bladder Anatomy

The bladder wall is composed of urothelium, lamina propria, muscularis propria, and adventitia/serosa
Clinical
─ Function: urine storage and expulsion
Macro
─ Hollow, distensible muscular organ; trigone is a triangular region at bladder base defined by ureteric orifices and internal urethral meatus
Micro
─ Urothelium (transitional epithelium): 2-7 cell layers thick; basal cells (cuboidal/columnar), intermediate cells, superficial umbrella cells (large, often bi/multinucleated, eosinophilic cytoplasm, flattened luminal surface)
─ Lamina propria: loose connective tissue, blood vessels, nerves, scattered inflammatory cells, muscularis mucosae (discontinuous smooth muscle bundles, not always well-defined)
─ Muscularis propria (detrusor muscle): thick bundles of smooth muscle arranged in inner longitudinal, middle circular, and outer longitudinal layers (interlacing, not always distinct)
─ Adventitia/Serosa: outer layer of loose connective tissue (adventitia) or mesothelial lining (serosa on superior surface)
Ancillary studies
─ IHC (Urothelium) (+): CK7, CK20 (superficial/umbrella cells), GATA3, p63 (basal/intermediate cells), Uroplakins (umbrella cells)
DDx
─ N/A for normal anatomy
Note
─ Reactive urothelium can show increased thickness, mild atypia, prominent nucleoli but maintains polarity and cohesion
─ Muscularis mucosae in lamina propria should not be confused with muscularis propria invasion
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Von Brunn Nests

Invaginations of normal urothelium into the superficial lamina propria; common incidental finding
Clinical
─ Asymptomatic, incidental
Micro
─ Solid nests or cords of urothelial cells within lamina propria, often connected to overlying surface urothelium
─ Cells are bland, identical to normal urothelium; orderly arrangement, smooth contours
─ No cytologic atypia, no stromal reaction beyond mild compression
Ancillary studies
─ IHC (+): p63, CK7, GATA3 (similar to normal urothelium)
DDx
─ Urothelial carcinoma, nested variant (Infiltrative growth, irregular nests, cytologic atypia, desmoplasia, loss of orderly pattern, often lacks p63 in invasive component)
─ Cystitis cystica/glandularis (Von Brunn nests with central lumina or glandular metaplasia)
Note
─ Benign; represent downgrowths of surface urothelium
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Cystitis Cystica

Von Brunn nests that have undergone cystic dilation, lined by urothelium
Clinical
─ Asymptomatic, incidental; may be associated with chronic inflammation or irritation
Micro
─ Cystically dilated spaces within lamina propria, lined by one to several layers of bland urothelial cells
─ Lumina may contain eosinophilic secretions
─ Often associated with Von Brunn nests and/or cystitis glandularis
Ancillary studies
─ IHC (+): p63, CK7, GATA3
DDx
─ Urothelial carcinoma with microcystic features (Cytologic atypia, infiltrative growth)
─ Nephrogenic adenoma (Tubules lined by hobnail cells, PAX8+)
Media ─ placeholder ─ Cystitis Cystica H&E ─ Cystitis cystica H&E

Cystitis Glandularis

Glandular metaplasia of urothelium, typically within Von Brunn nests or cystitis cystica; two types: non-mucinous (usual) and intestinal
Clinical
─ Asymptomatic, incidental; may be associated with chronic inflammation, irritation, or outlet obstruction
Micro
─ Gland-like structures in lamina propria lined by columnar or cuboidal cells
─ Usual/Non-mucinous type: Lined by columnar cells with eosinophilic cytoplasm, resembling urothelium with glandular change
─ Intestinal type: Lined by mucin-producing columnar cells, goblet cells, resembling intestinal epithelium; Paneth cells or neuroendocrine cells rare
─ May be associated with Von Brunn nests and cystitis cystica
Ancillary studies
─ Usual type IHC (+): p63 (often present), CK7, GATA3
─ Intestinal type IHC (+): CK20 (diffuse), CDX2; IHC (-/+): CK7 (may be patchy or neg), p63 (often neg or focal basal)
DDx
─ Adenocarcinoma of bladder (Invasive growth, significant cytologic atypia, desmoplastic stroma, complex architecture)
─ Villous adenoma (True neoplastic papillary lesion with glandular differentiation, dysplasia)
Note
─ Intestinal metaplasia is considered a risk factor for adenocarcinoma by some, but direct progression is rare
Media ─ placeholder ─ Cystitis glandularis H&E

Polypoid Cystitis

Exophytic, polypoid, bullous, or papillary inflammatory lesion of the bladder mucosa, often secondary to irritation or injury (e.g., indwelling catheters, stones, infection)
Clinical
─ Associated with chronic bladder irritation; may cause hematuria or obstructive symptoms
Macro
─ Polypoid, edematous, broad-based, or finger-like projections into bladder lumen
Micro
─ Broad, edematous fibrovascular cores lined by urothelium that may be normal, hyperplastic, or reactive
─ Lamina propria is edematous, inflamed (acute and/or chronic inflammatory cells), congested vessels
─ Urothelium may show some reactive atypia (enlarged nuclei, prominent nucleoli) but lacks features of papillary urothelial carcinoma (e.g., significant architectural disarray, loss of polarity, high-grade atypia)
─ No true delicate fibrovascular cores like in papillary urothelial neoplasms
Ancillary studies
─ IHC not usually required; urothelial markers as expected for reactive urothelium
DDx
─ Papillary urothelial carcinoma, low grade (More complex, delicate branching papillae, more architectural disarray, monotonous cells)
─ Papillary urothelial neoplasm of low malignant potential (PUNLMP) (Thickened urothelium on papillae, minimal atypia, more orderly than carcinoma)
─ Fibroepithelial polyp (More prominent stromal component, less inflammation usually)
Note
─ A reactive process, not neoplastic
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Follicular Cystitis

Chronic cystitis characterized by the presence of prominent lymphoid follicles with germinal centers in the lamina propria and sometimes muscularis propria

Clinical

─ Any age, F>M; associated with chronic UTI, bladder outlet obstruction, or prior instrumentation

─ Often asymptomatic; may cause irritative voiding symptoms or hematuria

Macro

─ Mucosa may appear normal, erythematous, granular, or nodular (due to submucosal follicles)

Micro

─ Presence of lymphoid follicles with well-formed germinal centers (tingible body macrophages, mitoses within germinal centers) and surrounding mantle zones in lamina propria

─ Overlying urothelium may be normal, reactive, or show squamous metaplasia

─ Variable chronic inflammatory infiltrate (lymphocytes, plasma cells) in surrounding stroma

Ancillary studies

─ IHC: Germinal centers BCL2-, CD10+, BCL6+; Mantle zones BCL2+, CD20+

DDx

─ Lymphoma involving bladder (Malignant lymphoid infiltrate, monotonous cells, destructive growth, specific lymphoma markers, light chain restriction if B-cell)

─ Chronic non-specific cystitis (Diffuse lymphoid infiltrate without well-formed germinal centers)

Note

─ A reactive lymphoid hyperplasia, not neoplastic

Media ─ placeholder ─ Malakoplakia and follicular cystitis H&E

Eosinophilic Cystitis

Rare inflammatory condition characterized by a dense transmural eosinophilic infiltrate in the bladder wall

Clinical

─ Any age, children and adults; M=F; etiology often unknown (idiopathic)

─ May be associated with allergic reactions, parasitic infections, drug reactions, or systemic eosinophilic syndromes

─ Presents with hematuria, dysuria, frequency, suprapubic pain; can mimic malignancy

Macro

─ Mucosa may be erythematous, edematous, ulcerated, or show polypoid/nodular masses

Micro

─ Dense, diffuse, or patchy infiltrate of eosinophils throughout lamina propria, muscularis propria, and sometimes perivesical fat

─ Variable numbers of lymphocytes, plasma cells, mast cells; edema, fibrosis, and muscle necrosis may be present

─ Urothelium may be ulcerated or show reactive changes

Ancillary studies

─ Peripheral blood eosinophilia may be present

─ Special stains for parasites if suspected

DDx

─ Allergic reaction/drug reaction (Clinical history)

─ Parasitic infection (e.g., Schistosomiasis - ova present)

─ Urothelial carcinoma with eosinophilic infiltrate (Presence of malignant urothelial cells)

─ Inflammatory myofibroblastic tumor (Spindle cell proliferation, ALK+ in some, eosinophils can be present)

Note

─ Diagnosis requires significant eosinophilic infiltrate and exclusion of other causes

─ Steroids are often used for treatment

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Encrusted Cystitis / Pyelitis (Alkaline Encrusted Cystitis)

Inflammatory condition characterized by precipitation of phosphate salts on ulcerated urothelium, often associated with urea-splitting bacterial infections

Clinical

─ Associated with chronic UTI by urea-splitting organisms (e.g., Proteus, Klebsiella, Corynebacterium urealyticum), alkaline urine pH

─ Indwelling catheters, immunosuppression, prior surgery are risk factors

─ Presents with hematuria, irritative symptoms, passage of "gravel" or calcified material

Macro

─ Whitish-gray, plaque-like, or nodular calcified deposits on an ulcerated and inflamed mucosal surface

Micro

─ Ulceration of urothelium with underlying granulation tissue and inflammation (acute and chronic)

─ Deposition of amorphous, basophilic, crystalline material (calcium phosphate, struvite) on the surface and within inflamed tissue

─ Bacteria may be visible within the encrustations

Ancillary studies

─ Urine culture for urea-splitting organisms

─ Urine pH (alkaline)

DDx

─ Malakoplakia (Michaelis-Gutmann bodies, different histiocyte morphology)

─ Calcified urothelial carcinoma (Malignant cells present)

─ Bladder stones (Free-lying calculi, not encrusted on wall typically)

Note

─ Treatment involves acidification of urine, antibiotics, and removal of encrustations

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Emphysematous Cystitis

Rare form of cystitis characterized by gas formation within the bladder wall and/or lumen, typically caused by gas-producing bacteria

Clinical

─ More common in elderly, diabetic patients (esp poorly controlled), immunocompromised individuals, or those with bladder outlet obstruction/neurogenic bladder

─ Common organisms: E. coli, Klebsiella pneumoniae, Enterobacter

─ Presents with dysuria, frequency, hematuria, pneumaturia (passage of gas in urine), abdominal pain

Macro

─ Cystoscopy may show edematous, erythematous mucosa with submucosal gas-filled cysts (blebs) or crepitus

─ Imaging (CT, X-ray) is diagnostic, showing gas in bladder wall/lumen

Micro

─ Acute and/or chronic inflammation of bladder wall

─ Presence of gas-filled cystic spaces (pseudocysts) within lamina propria, muscularis propria, or submucosa; these spaces lack an epithelial lining

─ Necrosis, edema, hemorrhage may be present; urothelial ulceration

Ancillary studies

─ Urine culture for gas-forming organisms

─ Imaging studies

DDx

─ Iatrogenic gas (e.g., post-instrumentation) (Clinical history)

─ Fistula to bowel (Clinical history, fecaluria)

Note

─ A potentially serious condition requiring prompt antibiotic therapy and management of underlying conditions (e.g., diabetes)

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Keratinizing Squamous Metaplasia (Leukoplakia of Bladder)

Replacement of urothelium by mature, keratinizing squamous epithelium

Clinical

─ Associated with chronic irritation, inflammation, infection (e.g., Schistosoma), stones, neurogenic bladder, vitamin A deficiency

─ M>F; may be asymptomatic or cause irritative symptoms, hematuria

─ Considered a potential premalignant lesion for squamous cell carcinoma by some, though risk is low

Macro

─ White, plaque-like lesions (leukoplakia) on cystoscopy; may be focal or extensive

Micro

─ Full-thickness replacement of urothelium by stratified squamous epithelium with surface keratinization (orthokeratosis or parakeratosis) and often a granular cell layer

─ Underlying lamina propria may show chronic inflammation and fibrosis

─ Cytologic atypia (dysplasia) may or may not be present within the squamous epithelium

Ancillary studies

─ IHC: Squamous epithelium p63+, HMWCK+, CK14+; GATA3-, CK7-, CK20- (usually)

DDx

─ Non-keratinizing squamous metaplasia (Lacks surface keratinization, less clinical significance)

─ Squamous dysplasia / Squamous cell carcinoma in situ (Significant cytologic atypia within squamous epithelium)

─ Invasive squamous cell carcinoma (Invasion into lamina propria)

Note

─ True keratinization (not just glycogenated squamous metaplasia) is required

─ Biopsy is needed to assess for atypia/dysplasia

Media ─ placeholder ─ Keratising squamous metaplasia WSI ─ Squamous metaplasia H&E

Malakoplakia

Uncommon chronic granulomatous inflammatory condition, most often affecting genitourinary tract, related to defective macrophage function in response to bacterial infection (typically E. coli)
Clinical
─ Bladder most common GU site; F>M; often associated with immunosuppression, chronic UTIs
─ May present as plaques, nodules, or ulcerated lesions; can mimic malignancy
Macro
─ Soft, yellowish-tan plaques or nodules on mucosal surface
Micro
─ Diffuse mucosal infiltrate of large, foamy histiocytes (von Hansemann cells) with granular eosinophilic cytoplasm
─ Michaelis-Gutmann bodies: Pathognomonic; laminated, targetoid, intracytoplasmic or extracellular basophilic inclusions (calcium and iron phosphate deposits on bacterial degradation products)
─ Variable lymphoplasmacytic infiltrate; fibrosis may be present
Ancillary studies
─ Special stains: PAS-D (+ in histiocytes and Michaelis-Gutmann bodies), von Kossa (+ for calcium in Michaelis-Gutmann bodies), Perls' iron stain (+ in Michaelis-Gutmann bodies)
─ IHC: Histiocytes CD68+
DDx
─ Xanthogranulomatous cystitis (Foamy histiocytes, but no Michaelis-Gutmann bodies, often associated with obstruction/stones)
─ Signet ring cell carcinoma (Malignant cells, mucin+, cytokeratin+)
─ Granulomatous inflammation, other types (e.g., TB, fungal - specific organisms, different type of granulomas)
Note
─ Diagnosis relies on identifying Michaelis-Gutmann bodies
Media ─ placeholder ─ Malakoplakia H&E ─ Malakoplakia H&E ─ Malakoplakia H&E ─ Malakoplakia H&E ─ Malakoplakia H&E ─ Malakoplakia WSI ─ Malakoplakia WSI ─ Malakoplakia WSI ─ Malakoplakia WSI

Follicular Cystitis

Chronic cystitis characterized by the presence of prominent lymphoid follicles with germinal centers in the lamina propria and sometimes muscularis propria
Clinical
─ Any age, F>M; associated with chronic UTI, bladder outlet obstruction, or prior instrumentation
─ Often asymptomatic; may cause irritative voiding symptoms or hematuria
Macro
─ Mucosa may appear normal, erythematous, granular, or nodular (due to submucosal follicles)
Micro
─ Presence of lymphoid follicles with well-formed germinal centers (tingible body macrophages, mitoses within germinal centers) and surrounding mantle zones in lamina propria
─ Overlying urothelium may be normal, reactive, or show squamous metaplasia
─ Variable chronic inflammatory infiltrate (lymphocytes, plasma cells) in surrounding stroma
Ancillary studies
─ IHC: Germinal centers BCL2-, CD10+, BCL6+; Mantle zones BCL2+, CD20+
DDx
─ Lymphoma involving bladder (Malignant lymphoid infiltrate, monotonous cells, destructive growth, specific lymphoma markers, light chain restriction if B-cell)
─ Chronic non-specific cystitis (Diffuse lymphoid infiltrate without well-formed germinal centers)
Note
─ A reactive lymphoid hyperplasia, not neoplastic
Media ─ placeholder ─ Malakoplakia and follicular cystitis H&E

Eosinophilic Cystitis

Rare inflammatory condition characterized by a dense transmural eosinophilic infiltrate in the bladder wall
Clinical
─ Any age, children and adults; M=F; etiology often unknown (idiopathic)
─ May be associated with allergic reactions, parasitic infections, drug reactions, or systemic eosinophilic syndromes
─ Presents with hematuria, dysuria, frequency, suprapubic pain; can mimic malignancy
Macro
─ Mucosa may be erythematous, edematous, ulcerated, or show polypoid/nodular masses
Micro
─ Dense, diffuse, or patchy infiltrate of eosinophils throughout lamina propria, muscularis propria, and sometimes perivesical fat
─ Variable numbers of lymphocytes, plasma cells, mast cells; edema, fibrosis, and muscle necrosis may be present
─ Urothelium may be ulcerated or show reactive changes
Ancillary studies
─ Peripheral blood eosinophilia may be present
─ Special stains for parasites if suspected
DDx
─ Allergic reaction/drug reaction (Clinical history)
─ Parasitic infection (e.g., Schistosomiasis - ova present)
─ Urothelial carcinoma with eosinophilic infiltrate (Presence of malignant urothelial cells)
─ Inflammatory myofibroblastic tumor (Spindle cell proliferation, ALK+ in some, eosinophils can be present)
Note
─ Diagnosis requires significant eosinophilic infiltrate and exclusion of other causes
─ Steroids are often used for treatment
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Encrusted Cystitis / Pyelitis (Alkaline Encrusted Cystitis)

Inflammatory condition characterized by precipitation of phosphate salts on ulcerated urothelium, often associated with urea-splitting bacterial infections
Clinical
─ Associated with chronic UTI by urea-splitting organisms (e.g., Proteus, Klebsiella, Corynebacterium urealyticum), alkaline urine pH
─ Indwelling catheters, immunosuppression, prior surgery are risk factors
─ Presents with hematuria, irritative symptoms, passage of "gravel" or calcified material
Macro
─ Whitish-gray, plaque-like, or nodular calcified deposits on an ulcerated and inflamed mucosal surface
Micro
─ Ulceration of urothelium with underlying granulation tissue and inflammation (acute and chronic)
─ Deposition of amorphous, basophilic, crystalline material (calcium phosphate, struvite) on the surface and within inflamed tissue
─ Bacteria may be visible within the encrustations
Ancillary studies
─ Urine culture for urea-splitting organisms
─ Urine pH (alkaline)
DDx
─ Malakoplakia (Michaelis-Gutmann bodies, different histiocyte morphology)
─ Calcified urothelial carcinoma (Malignant cells present)
─ Bladder stones (Free-lying calculi, not encrusted on wall typically)
Note
─ Treatment involves acidification of urine, antibiotics, and removal of encrustations
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Emphysematous Cystitis

Rare form of cystitis characterized by gas formation within the bladder wall and/or lumen, typically caused by gas-producing bacteria
Clinical
─ More common in elderly, diabetic patients (esp poorly controlled), immunocompromised individuals, or those with bladder outlet obstruction/neurogenic bladder
─ Common organisms: E. coli, Klebsiella pneumoniae, Enterobacter
─ Presents with dysuria, frequency, hematuria, pneumaturia (passage of gas in urine), abdominal pain
Macro
─ Cystoscopy may show edematous, erythematous mucosa with submucosal gas-filled cysts (blebs) or crepitus
─ Imaging (CT, X-ray) is diagnostic, showing gas in bladder wall/lumen
Micro
─ Acute and/or chronic inflammation of bladder wall
─ Presence of gas-filled cystic spaces (pseudocysts) within lamina propria, muscularis propria, or submucosa; these spaces lack an epithelial lining
─ Necrosis, edema, hemorrhage may be present; urothelial ulceration
Ancillary studies
─ Urine culture for gas-forming organisms
─ Imaging studies
DDx
─ Iatrogenic gas (e.g., post-instrumentation) (Clinical history)
─ Fistula to bowel (Clinical history, fecaluria)
Note
─ A potentially serious condition requiring prompt antibiotic therapy and management of underlying conditions (e.g., diabetes)
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Radiation Cystitis

Inflammatory and fibrotic changes in the bladder wall resulting from radiation therapy to the pelvis
Clinical
─ Occurs after pelvic irradiation for malignancies (e.g., prostate, cervical, rectal cancer)
─ Acute phase (during or shortly after RT): Dysuria, frequency, urgency, hematuria
─ Chronic phase (months to years after RT): Persistent symptoms, reduced bladder capacity, telangiectasias, hematuria, fistula formation
Macro
─ Acute: Mucosa erythematous, edematous, ulcerated
─ Chronic: Mucosa pale, atrophic, telangiectatic; bladder wall thickened, fibrotic
Micro
─ Acute: Urothelial edema, degeneration, atypia (enlarged, hyperchromatic nuclei, smudged chromatin - "radiation atypia"); mucosal ulceration, inflammation (neutrophils, lymphocytes)
─ Chronic: Submucosal fibrosis, hyalinization; atypical stromal fibroblasts (large, stellate, hyperchromatic, smudged nuclei - "radiation fibroblasts"); vascular changes (endothelial swelling, fibrinoid necrosis, hyalinization of vessel walls, telangiectasias); persistent urothelial atypia
Ancillary studies
─ Clinical history of radiation is key
DDx
─ Urothelial carcinoma in situ / Invasive carcinoma (True neoplastic atypia, different nuclear features, abnormal mitoses, Ki-67/p53 alterations; radiation atypia can be very difficult to distinguish)
─ Chemotherapy-induced cystitis (Similar changes, depends on agent)
Note
─ Radiation atypia in urothelial cells and stromal fibroblasts can be striking and mimic malignancy
─ Long-term risk of secondary malignancies (e.g., urothelial carcinoma, sarcoma)
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Keratinizing Squamous Metaplasia (Leukoplakia of Bladder)

Replacement of urothelium by mature, keratinizing squamous epithelium
Clinical
─ Associated with chronic irritation, inflammation, infection (e.g., Schistosoma), stones, neurogenic bladder, vitamin A deficiency
─ M>F; may be asymptomatic or cause irritative symptoms, hematuria
─ Considered a potential premalignant lesion for squamous cell carcinoma by some, though risk is low
Macro
─ White, plaque-like lesions (leukoplakia) on cystoscopy; may be focal or extensive
Micro
─ Full-thickness replacement of urothelium by stratified squamous epithelium with surface keratinization (orthokeratosis or parakeratosis) and often a granular cell layer
─ Underlying lamina propria may show chronic inflammation and fibrosis
─ Cytologic atypia (dysplasia) may or may not be present within the squamous epithelium
Ancillary studies
─ IHC: Squamous epithelium p63+, HMWCK+, CK14+; GATA3-, CK7-, CK20- (usually)
DDx
─ Non-keratinizing squamous metaplasia (Lacks surface keratinization, less clinical significance)
─ Squamous dysplasia / Squamous cell carcinoma in situ (Significant cytologic atypia within squamous epithelium)
─ Invasive squamous cell carcinoma (Invasion into lamina propria)
Note
─ True keratinization (not just glycogenated squamous metaplasia) is required
─ Biopsy is needed to assess for atypia/dysplasia
Media ─ placeholder ─ Keratising squamous metaplasia WSI ─ Squamous metaplasia H&E

Urothelial Tumors

Epidemiology/Risk Factors: Older individuals, M>F; smoking (most important); occupational exposure (aromatic amines, aniline dyes); pelvic radiation; cyclophosphamide; Schistosoma haematobium (assoc with SCC); chronic irritation
Molecular Pathways: Two main pathways often described:
─ Papillary pathway (FGFR3, TERT promoter mutations, Chr 9 loss) → PUNLMP, LGPUC → +/- progression to HGPUC, invasion
─ Flat pathway (TP53, RB1 mutations) → Urothelial dysplasia, CIS → HGPUC, invasion

Flat Urothelial Lesions

Spectrum from benign hyperplasia to carcinoma in situ (CIS), characterized by flat (non-papillary) urothelial proliferation with varying degrees of atypia
Micro
─ Urothelial Hyperplasia (Flat, without atypia): Increased number of cell layers (>7 layers) but cytologically bland, orderly maturation, no significant atypia
─ Reactive Urothelial Atypia: Cytologic changes (nuclear enlargement, hyperchromasia, prominent nucleoli) in context of inflammation or irritation; usually maintains polarity, atypia often diffuse, umbrella cells may be prominent/atypical
─ Urothelial Dysplasia (Low-grade intraurothelial neoplasia): Unequivocal cytologic atypia (nuclear crowding, hyperchromasia, irregular contours, loss of polarity) less severe than CIS; involves basal and intermediate layers, surface maturation usually present; umbrella cells may be lost
─ Carcinoma In Situ (CIS; High-grade intraurothelial neoplasia): Full-thickness or near full-thickness population of markedly atypical cells; large, pleomorphic, hyperchromatic nuclei, high N:C ratio, loss of polarity, mitoses (may be atypical, suprabasal); umbrella cell layer usually absent; may be denuding
Ancillary studies
─ CIS IHC (+): CK20 (often full thickness or strong patchy), p53 (often strong diffuse overexpression or complete absence - null pattern), Ki-67 (high proliferation index, often suprabasal)
─ Dysplasia: IHC less well-defined, may show patchy CK20/p53 abnormalities
DDx
─ Reactive atypia vs Dysplasia/CIS (Degree of atypia, loss of polarity, full-thickness involvement, IHC helpful)
─ Normal urothelium vs Hyperplasia (Cell layer count)
Note
─ CIS is a high-risk lesion for progression to invasive high-grade urothelial carcinoma
─ "Urothelial atypia of uncertain significance (AUS)" may be used for changes equivocal for reactive vs dysplasia
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Papillary Neoplasms

Papillary Urothelial Hyperplasia

A flat or slightly undulating urothelial proliferation with an increased number of cell layers, forming small, abortive papillary tufts lacking true fibrovascular cores
Clinical
─ Often an incidental finding; may be associated with inflammation or other urothelial neoplasms
Micro
─ Increased number of urothelial cell layers (>7) with minimal to no cytologic atypia
─ Small, broad-based, or slender non-vascularized papillary projections or undulations of the urothelium
─ Lacks well-formed, discrete fibrovascular cores seen in urothelial papilloma or papillary carcinoma
─ Cells are orderly, maintain polarity
Ancillary studies
─ IHC: Similar to normal urothelium (CK20 superficial, p63 basal/parabasal)
DDx
─ Urothelial papilloma (Discrete, delicate fibrovascular cores lined by normal-thickness urothelium)
─ Polypoid cystitis (Edematous stroma, inflammation, broader papillae, reactive urothelium)
─ Flat urothelial hyperplasia (Lacks even abortive papillary structures)
Note
─ Considered by some to be at the benign end of the spectrum of papillary lesions
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Urothelial Papilloma

Benign exophytic papillary neoplasm composed of delicate fibrovascular cores lined by urothelium of normal thickness and cytology
Clinical
─ Relatively uncommon; can occur at any age, M>F (approx 40-60s mentioned in user doc)
─ Often presents with hematuria; low risk of recurrence or progression
─ Inverted papilloma: Endophytic growth pattern of anastomosing cords/trabeculae of bland urothelium into lamina propria
Micro
─ Exophytic: Delicate, non-branching or sparsely branching papillary fronds with slender fibrovascular cores
─ Lined by normal-appearing urothelium (≤7 cell layers), normal maturation, no significant cytologic atypia; umbrella cells conspicuous
─ Inverted: Anastomosing cords and nests of bland urothelial cells growing down into lamina propria; smooth peripheral contours, no stromal invasion; may have microcysts
Ancillary studies
─ IHC (Exophytic): CK20 (+ in umbrella cells only), p63 (+ basal/parabasal), Ki-67 (low)
─ IHC (Inverted): CK20 (- or superficial), p63 (+), Ki-67 (low)
─ Molecular (Inverted): FGFR3 mutations common
DDx
─ Papillary urothelial neoplasm of low malignant potential (PUNLMP) (Thicker urothelial lining >7 layers, monotonous cells)
─ Low-grade papillary urothelial carcinoma (Thicker urothelium, mild cytologic/architectural atypia, more complex branching)
─ Polypoid cystitis (Broader papillae, stromal edema, inflammation)
Note
─ Atypical umbrella cells are allowed in exophytic papilloma
Media ─ placeholder ─ Inverted urothelial papilloma H&E ─ Inverted urothelial papilloma H&E

Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP)

Papillary urothelial tumor with thicker urothelial lining than papilloma, but minimal to no cytologic atypia; has a low risk of recurrence and progression to higher grade/stage
Clinical
─ Adults (mean age ~60s), M>F; presents with hematuria
─ Excluded if prior history of urothelial carcinoma
Micro
─ Orderly papillary structures with fibrovascular cores; urothelial lining is thicker than normal (>7 cell layers)
─ Cells are monotonous, with minimal cytologic atypia; nuclei may be slightly enlarged but are uniform, round to oval, with smooth contours and inconspicuous nucleoli
─ Polarity is generally maintained; mitoses are rare and basal
─ Umbrella cell layer may be present or attenuated
Ancillary studies
─ IHC: CK20 (often superficial or patchy, not full thickness), p63 (basal/parabasal), Ki-67 (low, basal)
─ Molecular: FGFR3 and TERT promoter mutations common; Chr 9 loss
DDx
─ Urothelial papilloma (Urothelial lining ≤7 layers thick)
─ Low-grade papillary urothelial carcinoma (Mild but definite cytologic atypia, nuclear crowding, slight irregularity of nuclear size/shape, more architectural complexity)
─ Papillary urothelial hyperplasia (Lacks true fibrovascular cores, less urothelial thickening usually)
Note
─ Represents a lesion with neoplastic potential but very low risk of progression
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Non-Invasive Papillary Urothelial Carcinoma

Malignant papillary neoplasm of the urothelium characterized by architectural and/or cytologic atypia, confined to the epithelium (no invasion into lamina propria)
Clinical
─ Bladder, renal pelvis, ureter, urethra; older adults (mean age 70s), M>F
─ Presents with hematuria; risk of recurrence and progression (to higher grade or stage)
─ Divided into Low-Grade (LGPUC) and High-Grade (HGPUC)
Macro
─ Exophytic, papillary, or sessile lesions; may be single or multiple; variable size
Micro
─ Low-Grade Papillary Urothelial Carcinoma (LGPUC):
─ Orderly papillary structures with fibrovascular cores; urothelial lining is usually thickened
─ Mild to moderate variation in nuclear size, shape, and chromatin; nuclei generally round to oval, minimal pleomorphism
─ Polarity often maintained but may show some disarray; mitoses infrequent, usually basal
─ Umbrella cell layer often absent or attenuated
─ High-Grade Papillary Urothelial Carcinoma (HGPUC):
─ Disordered papillary structures, often with fused papillae, complex branching, or solid areas
─ Marked cytologic atypia: significant nuclear pleomorphism, irregular nuclear contours, coarse chromatin, prominent/irregular nucleoli, high N:C ratio
─ Loss of polarity is common; mitoses frequent, often atypical and suprabasal
─ Necrosis may be present
Ancillary studies
─ LGPUC IHC: CK20 (often patchy or superficial), p63 (basal/parabasal), Ki-67 (low, basal)
─ HGPUC IHC: CK20 (often strong, diffuse, or full-thickness), p53 (often strong diffuse overexpression or null pattern), Ki-67 (high, often suprabasal)
─ General Urothelial Markers: GATA3 (+), HMWCK (+), CK7 (+)
─ Molecular (LGPUC): FGFR3 and TERT promoter mutations common, Chr 9 loss
─ Molecular (HGPUC): TP53 and RB1 mutations more common, complex karyotypes
DDx
─ Papillary urothelial neoplasm of low malignant potential (PUNLMP) (Minimal atypia, more orderly than LGPUC)
─ Urothelial papilloma (Normal urothelial thickness and cytology)
─ Reactive atypia/Polypoid cystitis (Inflammation, edema, less architectural complexity, lacks true neoplastic atypia)
─ Carcinoma in situ (CIS) (Flat lesion with high-grade atypia, may coexist with HGPUC)
Note
─ Grade is based on the highest degree of architectural and cytologic atypia (highest 5% component per user doc, though generally overall impression)
─ HGPUC has a significant risk of progression to invasive carcinoma
Media ─ placeholder ─ Papillary urothelial carcinoma combined with giant cell tumour H&E

Urothelial Proliferation of Uncertain Malignant Potential (UPUMP)

A flat or slightly undulating urothelial proliferation that is thickened and shows clonal cytologic alterations, but lacks sufficient atypia for a definitive diagnosis of urothelial dysplasia or carcinoma in situ; rarely used diagnosis
Clinical
─ Bladder; significance and natural history are not well defined
Micro
─ Urothelium is thickened (>7 cell layers), may be flat or slightly undulating
─ Cytologic atypia is mild, exceeding reactive changes but insufficient for dysplasia/CIS
─ Cells may appear monotonous or show slight nuclear enlargement/hyperchromasia
─ Polarity usually maintained; mitoses rare
Ancillary studies
─ IHC and molecular findings are not well characterized or standardized for this category
DDx
─ Flat urothelial hyperplasia (Thickened but cytologically bland)
─ Reactive urothelial atypia (Atypia clearly related to inflammation/injury)
─ Urothelial dysplasia (More definite, unequivocal cytologic atypia)
Note
─ A diagnosis of exclusion, used sparingly when changes cannot be confidently classified as benign/reactive or neoplastic (dysplasia/CIS)
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Invasive Urothelial Carcinoma

Malignant urothelial neoplasm that has invaded beyond the basement membrane into the lamina propria or deeper structures
Clinical
─ Bladder, renal pelvis, ureter, urethra; older adults, M>F
─ Presents with hematuria, irritative voiding symptoms, flank pain (upper tract)
─ Prognosis depends on grade, depth of invasion (stage), presence of lymphovascular invasion, and histologic variants
Macro
─ May be papillary, nodular, flat, or ulcerated; often firm and infiltrative
Micro
─ Infiltrating nests, cords, trabeculae, or single cells of malignant urothelial cells into lamina propria, muscularis propria, or beyond
─ Cytology is usually high-grade (similar to HGPUC or CIS), with nuclear pleomorphism, hyperchromasia, prominent nucleoli, mitoses
─ Stromal response varies (desmoplastic, myxoid, inflammatory)
─ Lymphovascular invasion is common and an adverse prognostic factor
─ Invasion patterns: Infiltrating nests, single cells, micropapillary, plasmacytoid, etc
─ Divergent Differentiation: Common; urothelial carcinoma with areas of squamous, glandular, trophoblastic, or other differentiation
─ Squamous: Intercellular bridges, keratinization
─ Glandular: True gland formation, may resemble enteric adenocarcinoma
─ Trophoblastic: Syncytiotrophoblasts, cytotrophoblasts, may secrete β-hCG
─ Histologic Variants (can impact prognosis/treatment): Nested, Micropapillary, Plasmacytoid, Sarcomatoid, Lymphoepithelioma-like, Clear cell, Lipid-rich, etc
Ancillary studies
─ IHC (+): GATA3, p63/p40 (p40 more specific for urothelial vs prostatic), CK7, CK20 (variable, often + in invasive), Uroplakin III (less sensitive but specific), Thrombomodulin, S100P
─ IHC for staging: Smooth muscle actin or desmin can highlight muscularis propria to assess depth of invasion if uncertain (but IHC not recommended for MP vs LP invasion per user doc)
DDx
─ Benign reactive processes with pseudoinfiltration (e.g., florid Von Brunn nest proliferation, nephrogenic adenoma) (Lack significant atypia, specific markers like PAX8 for nephrogenic adenoma)
─ Metastatic carcinoma (Clinical history, IHC profile of primary, e.g., PSA for prostate, CDX2 for colorectal)
─ Other primary bladder tumors (e.g., SCC, adenocarcinoma - distinct morphology and IHC)
Note
─ Staging (TNM) is critical: pTa (non-invasive papillary), pTis (CIS), pT1 (lamina propria invasion), pT2 (muscularis propria invasion), pT3 (perivesical tissue invasion), pT4 (adjacent organ invasion)
─ Micropapillary and plasmacytoid variants are particularly aggressive
Media ─ placeholder ─ Carcinoma (urothelial carcinoma with squamous differention +/- lymphoepitheiial, poorly differentiated tumour with squamous differentiation, squamous cell carcinoma and lymphoepithelial SCC) H&E ─ G3 (WHO high grade) invasive urothelial carcinoma with micropapillary and probable lipid rich components.Urothelial carcinoma with clear cell change H&E ─ Urothelial carcinoma H&E ─ Urothelial carcinoma (grade 3) H&E

Other Urothelial Tumors

Squamous Cell Carcinoma (SCC)

Malignant epithelial neoplasm showing pure squamous differentiation, without evidence of urothelial carcinoma
Clinical
─ Bladder; less common than urothelial carcinoma in Western countries, more common in regions with endemic Schistosoma haematobium infection
─ Risk factors: Chronic irritation, infection (Schistosoma), stones, indwelling catheters, cyclophosphamide
─ Generally presents at advanced stage; poorer prognosis than urothelial carcinoma
Macro
─ Often large, ulcerated, infiltrative, or exophytic friable mass
Micro
─ Infiltrating nests, sheets, or cords of malignant squamous cells
─ Characterized by intercellular bridges (desmosomes) and/or keratinization (keratin pearls, individual cell keratinization)
─ Cells are polygonal with abundant eosinophilic cytoplasm, enlarged pleomorphic nuclei, prominent nucleoli; mitoses frequent
─ No urothelial component (by definition for pure SCC)
Ancillary studies
─ IHC (+): p63, p40, HMWCK (CK5/6, 34βE12), CK14, EMA
─ IHC (-): GATA3 (usually), CK7 (often), CK20 (often), PSA, PSAP, Uroplakins
DDx
─ Invasive urothelial carcinoma with extensive squamous differentiation (Must identify areas of conventional urothelial carcinoma or CIS; GATA3 often + in urothelial component)
─ Metastatic SCC from another site (e.g., cervix, lung, skin) (Clinical history, HPV status for cervical origin)
─ Verrucous carcinoma (Well-differentiated variant of SCC, pushing borders, minimal atypia)
Note
─ Pure SCC diagnosis requires thorough sampling to exclude a urothelial component
Media ─ placeholder ─ squamous cell carcinoma H&E

Neuroendocrine Carcinoma (NEC)

High-grade malignant epithelial neoplasm with neuroendocrine differentiation, encompassing small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC)
Clinical
─ Bladder; rare, M>F, older adults
─ SCNEC more common than LCNEC; often associated with conventional urothelial carcinoma (mixed tumors)
─ Highly aggressive with early metastasis; poor prognosis
─ May present with hematuria, obstructive symptoms, or paraneoplastic syndromes (less common)
Macro
─ Often large, infiltrative mass; may be polypoid or ulcerated; hemorrhage and necrosis common
Micro
─ Small Cell Neuroendocrine Carcinoma (SCNEC):
─ Sheets, nests, or diffuse infiltrates of small, round to oval cells with scant cytoplasm
─ Nuclei: Hyperchromatic, finely granular (salt-and-pepper) chromatin, inconspicuous nucleoli, nuclear molding common
─ High mitotic rate (numerous mitoses, often atypical); extensive apoptosis and necrosis (comedo-type)
─ Large Cell Neuroendocrine Carcinoma (LCNEC):
─ Nests, trabeculae, or sheets of large polygonal cells with more abundant eosinophilic or amphophilic cytoplasm
─ Nuclei: Vesicular or coarse chromatin, prominent nucleoli; high N:C ratio
─ High mitotic rate; geographic necrosis common; organoid or rosette-like structures may be seen
─ Both types often show extensive lymphovascular invasion
Ancillary studies
─ IHC (+): Neuroendocrine markers (at least one, usually multiple): Synaptophysin (diffuse granular cytoplasmic), Chromogranin A (cytoplasmic, may be focal), CD56 (NCAM, membranous)
─ IHC (+ for SCNEC/LCNEC): TTF-1 (often positive in SCNEC, variable in LCNEC), Ki-67 (very high proliferation index, >50-70%)
─ IHC (Variable): Cytokeratins (AE1/AE3, CAM5.2 - often dot-like or weak), p63 (usually -), GATA3 (usually -)
─ If mixed with urothelial carcinoma, urothelial component will be positive for GATA3, p63, CK7/20 as expected
DDx
─ High-grade urothelial carcinoma (Lacks definitive neuroendocrine morphology and markers; GATA3+, p63+)
─ Lymphoma (Hematopoietic markers+, LCA+, CD20+, CD3+ etc.; NE markers-)
─ Metastatic neuroendocrine carcinoma (e.g., from lung) (Clinical history, imaging; PAX8- if lung primary)
─ Well-differentiated neuroendocrine tumor (Carcinoid) (Organoid pattern, less atypia, lower Ki-67, different prognosis)
Note
─ SCNEC of bladder is histologically and immunophenotypically similar to SCNEC of lung
─ Presence of any NEC component in a urothelial carcinoma worsens prognosis
Media ─ placeholder ─ Primary prostatic neuroendocrine carcinoma / small cell H&E ─ Small cell/neuroendocrine carcinoma H&E

Well-Differentiated Neuroendocrine Tumor (Carcinoid Tumor)

Low-grade malignant epithelial neoplasm with neuroendocrine differentiation, morphologically similar to carcinoid tumors of other sites
Clinical
─ Bladder; extremely rare
─ May be asymptomatic, cause hematuria, or rarely carcinoid syndrome if functional
─ Generally indolent behavior, but can metastasize (regional nodes, liver)
Macro
─ Usually small, submucosal nodule or polyp; yellowish-tan
Micro
─ Organoid, nested, trabecular, or gyriform growth patterns; cells separated by delicate fibrovascular stroma
─ Uniform, polygonal cells with moderate amounts of eosinophilic, finely granular cytoplasm
─ Nuclei: Round to oval, "salt-and-pepper" (stippled) chromatin, inconspicuous nucleoli
─ Mitotic activity is low (<2 mitoses/10 HPF); necrosis usually absent
Ancillary studies
─ IHC (+): Synaptophysin (strong diffuse), Chromogranin A (strong diffuse), CD56 (variable)
─ IHC (+): Cytokeratins (often dot-like), Ki-67 (low proliferation index, typically <2-3%)
─ IHC (-): p63, GATA3 (or weak/focal), TTF-1 (usually)
DDx
─ Neuroendocrine carcinoma (SCNEC/LCNEC) (High-grade atypia, high mitotic rate, necrosis, high Ki-67)
─ Paraganglioma (Nests of chief cells (NE markers+) and sustentacular cells (S100+); lacks cytokeratin)
─ Metastatic well-differentiated NET from other site (e.g., GI, lung) (Clinical history, specific markers like CDX2 for GI, Islet-1 for pancreatic)
─ Florid Von Brunn nest proliferation or cystitis glandularis (Can have nested appearance but lacks NE markers, p63/GATA3+)
Note
─ True carcinoid tumors of the bladder are exceptionally rare; most bladder NETs are high-grade NECs
Media ─ placeholder ─ Carcinoid tumour H&E ─ Carcinoid tumour H&E

Nephrogenic Adenoma

Benign, metaplastic-appearing lesion of urothelium, often secondary to chronic irritation, inflammation, or prior surgery/instrumentation; composed of small tubules, papillae, or cysts
Clinical
─ Bladder, urethra, ureter; any age, M>F
─ Associated with prior urothelial injury (e.g., BCG therapy, trauma, stones, catheters)
─ Presents with hematuria, irritative symptoms, or as incidental finding; can recur but is benign
Macro
─ Small, polypoid, papillary, velvety, or sessile lesion; may be multiple
Micro
─ Variable patterns:
─ Small tubules/acini: Most common; small, closely packed tubules lined by cuboidal, hobnail, or flattened cells
─ Papillary: Delicate papillae lined by similar cells
─ Cystic: Dilated tubules or cysts
─ Solid/Sheets: Less common
─ Cells: Cuboidal, columnar, hobnail, or clear cells; cytoplasm eosinophilic, clear, or vacuolated; nuclei round, bland, may have small nucleoli; atypia usually minimal but can be reactive
─ Stroma: Often edematous, inflamed (acute/chronic), or hyalinized; thick eosinophilic basement membrane material around tubules can be prominent
─ "Fibromyxoid variant" shows prominent myxoid stroma
Ancillary studies
─ IHC (+): PAX8 (nuclear, strong diffuse - key marker), PAX2, AMACR (P504S, variable), CK7
─ IHC (-): p63 (usually), GATA3 (usually), PSA, Uroplakins (usually)
DDx
─ Clear cell carcinoma of bladder/urethra (Malignant atypia, infiltrative growth, PAX8+, but more pleomorphism, mitoses)
─ Urothelial carcinoma with glandular or clear cell features (GATA3+, p63+, lacks diffuse PAX8)
─ Prostatic adenocarcinoma involving bladder (PSA+, NKX3.1+, PAX8-)
─ Cystitis cystica/glandularis (Lined by urothelial or glandular cells, PAX8-, p63/GATA3+)
Note
─ PAX8 positivity is a very useful diagnostic feature
─ Despite sometimes worrisome patterns (e.g., "signet ring-like" cells due to mucin), it is benign
Media ─ placeholder ─ Focal nephrogenic adenoma H&E H&E CK05 P63 ─ Nephrogenic Adenoma / Metaplasia H&E ─ Nephrogenic adenoma H&E

Villous Adenoma and Adenocarcinoma (Primary Bladder Adenocarcinoma, Non-Urachal)

Villous Adenoma

Benign glandular neoplasm resembling colorectal villous adenoma, extremely rare in bladder
Clinical
─ Bladder; older adults
─ May present with hematuria or mucous discharge
─ Considered premalignant, can be associated with or progress to adenocarcinoma
Macro
─ Exophytic, papillary, velvety, or cauliflower-like mass
Micro
─ Long, finger-like villous projections lined by dysplastic columnar mucinous epithelium (resembling colonic adenoma)
─ Cells are tall columnar, pseudostratified, with elongated hyperchromatic nuclei; goblet cells common
─ Variable degrees of dysplasia (low-grade to high-grade)
─ No invasion into lamina propria (by definition for pure adenoma)
Ancillary studies
─ IHC (+): CK20 (diffuse), CDX2 (nuclear), MUC2 (goblet cells)
─ IHC (-/+): CK7 (often negative or patchy, unlike most urothelial lesions), β-catenin (nuclear staining suggests Wnt pathway activation)
─ IHC (-): p63, GATA3, Uroplakins
DDx
─ Cystitis glandularis, intestinal type (Metaplastic, lacks complex villous architecture and significant dysplasia of adenoma)
─ Adenocarcinoma arising in villous adenoma (Evidence of invasion)
─ Metastatic colorectal adenocarcinoma (Clinical history, identical morphology/IHC)
Note
─ Must be distinguished from adenocarcinoma arising from intestinal metaplasia or urachal remnants
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Adenocarcinoma, Non-Urachal (Primary Bladder Adenocarcinoma)

Malignant glandular neoplasm arising from bladder urothelium (not from urachus), often associated with intestinal metaplasia or cystitis glandularis
Clinical
─ Bladder; rare (<2% of bladder cancers); older adults
─ Risk factors: Chronic irritation, exstrophy, schistosomiasis, previous cystoplasty
─ Often presents at advanced stage; prognosis generally poorer than urothelial carcinoma
Macro
─ Polypoid, nodular, ulcerated, or infiltrative mass; may be mucinous
Micro
─ Various histologic types, resembling adenocarcinomas of other sites:
─ Intestinal-type (colonic-type): Most common; glands, cribriform structures, or signet ring cells resembling colorectal cancer
─ Mucinous: Abundant extracellular mucin (colloid carcinoma)
─ Signet ring cell: Predominance of signet ring cells (>50%)
─ Clear cell: (Discussed separately if Mullerian origin)
─ Hepatoid, not otherwise specified
─ Invasion into lamina propria or deeper
Ancillary studies
─ Intestinal-type IHC (+): CK20 (diffuse), CDX2 (nuclear), Villin
─ IHC (-/+): CK7 (often negative or patchy, helps distinguish from urothelial carcinoma with glandular differentiation which is usually CK7+), GATA3 (usually -), p63 (usually -)
─ Signet ring cells: Mucin stains (Alcian blue, PAS-D)
DDx
─ Metastatic adenocarcinoma (esp colorectal, prostate, gynecologic) (Clinical history, IHC profile: e.g., PSA for prostate; PAX8, ER/PR for GYN; SATB2 for lower GI)
─ Urothelial carcinoma with glandular differentiation (Areas of conventional urothelial ca or CIS, GATA3+, CK7 often diffuse)
─ Urachal adenocarcinoma (Location at dome/anterior wall, epicenter in wall, specific histology)
─ Villous adenoma (Lacks invasion)
─ Nephrogenic adenoma (PAX8+, bland cytology)
Note
─ Diagnosis of primary bladder adenocarcinoma requires exclusion of metastasis and urachal origin
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Urachal Carcinoma (Predominantly Adenocarcinoma)

Malignant epithelial neoplasm arising from urachal remnants, typically located in the bladder dome or anterior wall
Clinical
─ Bladder dome or anterior wall midline; older adults (mean 50-60s), M>F
─ Often presents late with hematuria, mucosuria, pain, or umbilical discharge; aggressive, poor prognosis
─ Criteria for diagnosis: Location in dome/anterior wall; epicenter in bladder wall (not primarily mucosal); absence of widespread cystitis cystica/glandularis away from tumor; absence of other known primary adenocarcinoma
Macro
─ Tumor in bladder dome/anterior wall, often involving muscularis propria or extending into perivesical tissue/umbilicus; may be solid, cystic, or mucinous
Micro
─ Adenocarcinoma is most common type (>90%); usually mucinous (colloid) or intestinal-type (enteric)
─ Mucinous adenocarcinoma: Abundant extracellular mucin lakes with floating tumor cells/glands
─ Intestinal-type: Glands resembling colorectal adenocarcinoma, may have dirty necrosis
─ Other rare types: Squamous cell carcinoma, neuroendocrine carcinoma, sarcomatoid carcinoma
─ Often infiltrates deeply into bladder wall and surrounding structures; surface urothelium may be intact or ulcerated
─ May arise from urachal remnants (columnar or transitional epithelium within bladder wall)
Ancillary studies
─ Adenocarcinoma IHC (+): CK20 (diffuse), CDX2 (nuclear), MUC2 (for mucinous types)
─ IHC (-/+): CK7 (often negative or patchy, unlike most primary bladder urothelial or non-urachal adenocarcinomas which are CK7+); β-catenin (nuclear staining variable)
─ IHC (-): GATA3, p63, Uroplakins (to distinguish from urothelial origin)
DDx
─ Primary non-urachal bladder adenocarcinoma (Different location, often associated with extensive cystitis glandularis/intestinal metaplasia, CK7 often +)
─ Metastatic colorectal adenocarcinoma (Clinical history, identical morphology/IHC, but urachal can be indistinguishable by IHC alone)
─ Urothelial carcinoma with glandular differentiation (Urothelial component elsewhere, GATA3+, CK7+)
Note
─ Diagnosis relies heavily on location and excluding other primaries
─ Often presents at higher stage due to intramural origin
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Clear Cell Carcinoma (of Bladder/Urethra)

Rare aggressive adenocarcinoma of the female urethra and bladder (less commonly in males), thought to be of Mullerian origin or from nephrogenic adenoma precursors
Clinical
─ Predominantly females, urethra > bladder; older adults (mean 60s)
─ Presents with hematuria, dysuria, mass; aggressive with high rates of recurrence and metastasis
─ May be associated with endometriosis or Mullerianosis
Macro
─ Polypoid, nodular, or infiltrative mass; tan-yellow or gray
Micro
─ Various architectural patterns:
─ Tubulocystic: Tubules and cysts lined by clear, hobnail, or flattened cells (most common)
─ Papillary: Papillary fronds lined by similar cells
─ Solid/Diffuse: Sheets of clear cells
─ Cells: Polygonal with abundant clear cytoplasm (glycogen-rich), or hobnail cells with prominent nuclei bulging into lumina
─ Marked cytologic atypia: Large, hyperchromatic, pleomorphic nuclei; prominent nucleoli; mitoses often frequent
─ Hyalinized or fibrotic stroma common
Ancillary studies
─ IHC (+): PAX8 (nuclear, strong), Napsin A (cytoplasmic), AMACR (P504S), HNF-1β (nuclear), CK7
─ IHC (-/+): CA-125 (variable), ER/PR (variable)
─ IHC (-): GATA3, p63, Uroplakins, CK20, PSA
DDx
─ Nephrogenic adenoma (PAX8+, but bland cytology, lacks significant atypia/invasion)
─ Urothelial carcinoma with clear cell features (GATA3+, p63+, lacks diffuse PAX8/Napsin A)
─ Metastatic clear cell renal cell carcinoma (PAX8+, CAIX+, CD10+; clinical history)
─ Metastatic clear cell carcinoma from gynecologic tract (PAX8+, ER/PR often +, WT1 often + for ovarian serous)
Note
─ Histologically similar to clear cell carcinomas of ovary, endometrium, cervix, and vagina
─ Mullerian origin is favored for most cases
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Paraganglioma (of Bladder)

Rare neuroendocrine neoplasm arising from paraganglia of the autonomic nervous system within the bladder wall; most are benign, but ~10-15% can be malignant
Clinical
─ Bladder wall, any location but often trigone/lateral walls; wide age range, M=F
─ May be functional (catecholamine-secreting), causing hypertensive crisis, palpitations, headache, sweating, esp during micturition ("micturition syncope")
─ Non-functional tumors present with hematuria or as incidental finding
─ Malignancy defined by metastases (regional nodes, distant sites); histologic features unreliable for predicting behavior
Macro
─ Well-circumscribed, firm, submucosal nodule; yellow-tan, red-brown, or gray; variable size
Micro
─ Nested or alveolar ("Zellballen") pattern: Nests of chief cells (polygonal, granular eosinophilic/amphophilic cytoplasm, round "salt-and-pepper" nuclei) surrounded by delicate fibrovascular stroma
─ Sustentacular cells: Spindle-shaped cells at periphery of nests, often inconspicuous on H&E
─ Cytoplasm of chief cells may be clear or oncocytic; nuclear pleomorphism can be present but doesn't reliably predict malignancy
─ Mitoses usually rare; necrosis uncommon in benign lesions
Ancillary studies
─ Chief cells IHC (+): Chromogranin A, Synaptophysin, Neuron-specific enolase (NSE), CD56
─ Sustentacular cells IHC (+): S100 protein, SOX10, GFAP (highlights network around nests)
─ IHC (-): Cytokeratins (AE1/AE3, CAM5.2 - characteristically negative in chief cells), PAX8, GATA3
─ SDHB IHC: Loss of staining suggests SDH deficiency (associated with hereditary paraganglioma syndromes and increased metastatic risk)
DDx
─ Urothelial carcinoma, nested or with clear cell features (Cytokeratin+, GATA3+, S100-, NE markers-)
─ Granular cell tumor (S100+, PAS-D+ granules, different morphology)
─ Melanoma (S100+, SOX10+, HMB45/Melan-A+, NE markers-)
─ Well-differentiated neuroendocrine tumor (Carcinoid) (Cytokeratin+, S100- sustentacular cells absent)
Note
─ Most bladder paragangliomas are non-functional
─ SDHB immunohistochemistry is recommended for all paragangliomas
Media ─ placeholder ─ Paraganglioma H&E

Leiomyosarcoma

Malignant mesenchymal neoplasm showing smooth muscle differentiation

Clinical

─ Bladder; rare primary tumor, more common in adults (mean age 50-60s), M>F

─ May arise de novo or from pre-existing leiomyoma (rare); can be associated with prior cyclophosphamide or radiation

─ Presents with hematuria, dysuria, palpable mass, obstructive symptoms; aggressive, high rates of recurrence and metastasis

Macro

─ Large, fleshy, firm or soft mass; may be polypoid, intramural, or extruding from bladder; gray-white to tan; hemorrhage and necrosis common

Micro

─ Intersecting fascicles of spindle cells with eosinophilic, fibrillar cytoplasm and elongated, blunt-ended ("cigar-shaped") nuclei

─ Significant cytologic atypia: Nuclear pleomorphism, hyperchromasia, irregular nuclear contours

─ High mitotic activity (e.g., >10 mitoses/10 HPF), atypical mitotic figures common

─ Coagulative tumor necrosis is often present

─ Grading (e.g., FNCLCC system) based on differentiation, mitotic count, and necrosis

Ancillary studies

─ IHC (+): Smooth muscle actin (SMA, often diffuse), Muscle-specific actin (MSA), Desmin (often diffuse), Caldesmon (h-caldesmon)

─ IHC (-/+): Cytokeratins (can be focally positive in ~30%, potential pitfall), S100 (usually negative), CD117 (usually negative), ALK (negative)

DDx

─ Sarcomatoid urothelial carcinoma (Malignant epithelial component often present or by history, cytokeratin/GATA3/p63+ in epithelial part)

─ Inflammatory myofibroblastic tumor (IMT) (Less atypia, prominent inflammatory infiltrate, ALK+ in ~50%)

─ Leiomyoma (Bland cytology, low/absent mitotic activity, no necrosis)

─ Other spindle cell sarcomas (e.g., MPNST - S100+; Undifferentiated pleomorphic sarcoma - diagnosis of exclusion)

Note

─ Most common sarcoma of the adult bladder

─ Prognosis depends on tumor size, grade, and stage

Media ─ placeholder ─ Paraganglioma H&E

Inflammatory Myofibroblastic Tumor (IMT)

Mesenchymal neoplasm of intermediate (rarely metastasizing) malignant potential, composed of myofibroblastic spindle cells with a prominent inflammatory infiltrate
Clinical
─ Bladder most common GU site; children and young adults, but any age; M>F
─ Presents with hematuria, irritative symptoms, pelvic mass; may be related to prior surgery, trauma, or infection
─ Most behave benignly after complete excision; recurrences can occur, metastases rare
Macro
─ Well-circumscribed or infiltrative fleshy, firm mass; tan-white or yellowish; variable size
Micro
─ Spindle to stellate myofibroblastic cells arranged in fascicles or haphazardly, often in a loose, myxoid, or edematous stroma
─ Prominent inflammatory infiltrate: Plasma cells, lymphocytes, eosinophils, histiocytes
─ Tumor cells: Plump spindle cells with vesicular nuclei, small nucleoli, eosinophilic cytoplasm; atypia usually mild, mitoses variable but typically low
─ Vascularity can be prominent; ganglion-like cells may be seen
─ Three main histologic patterns described: Myxoid/vascular (most common in bladder), compact spindle cell, hypocellular fibrous
Ancillary studies
─ IHC (+): Smooth muscle actin (SMA, often diffuse), Muscle-specific actin (MSA), Desmin (variable), ALK (anaplastic lymphoma kinase, cytoplasmic staining in ~50-60%, correlates with ALK gene rearrangement)
─ IHC (-/+): Cytokeratins (can be focally positive, esp dot-like), CD34 (variable)
─ IHC (-): S100, Myogenin
─ Molecular: ALK gene (2p23) rearrangements common (esp with RANBP2, CLTC)
DDx
─ Sarcomatoid urothelial carcinoma (Marked atypia, malignant epithelial component often present, GATA3/p63/CK+ in epithelial part, ALK-)
─ Leiomyosarcoma (More cytologic atypia, higher mitotic rate, desmin usually strong diffuse, ALK-)
─ Rhabdomyosarcoma (esp embryonal in children) (Myogenin+, MyoD1+, ALK-)
─ Polypoid cystitis with prominent stroma (Less cellular stroma, more superficial, lacks ALK rearrangement)
Note
─ Also known as inflammatory pseudotumor or plasma cell granuloma (older terms)
─ ALK positivity is a helpful diagnostic marker and generally associated with better prognosis
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Prostate

Benign Prostate

Normal Prostate

The prostate is a fibromuscular glandular organ surrounding the male urethra at the base of the bladder
Clinical
─ Function: contributes alkaline fluid to semen
Macro
─ Chestnut-shaped organ; ~20 grams in young adults; enlarges with age (benign prostatic hyperplasia)
─ Zonal anatomy: Peripheral zone (PZ, ~70%, site of most carcinomas); Central zone (CZ, ~25%, surrounds ejaculatory ducts, resistant to carcinoma); Transition zone (TZ, ~5%, surrounds urethra, site of BPH); Anterior fibromuscular stroma (AFMS, ~5%, non-glandular)
Micro
─ Composed of glands and fibromuscular stroma
─ Glands: Tubuloalveolar structures; lined by two cell layers: inner/luminal secretory columnar cells (abundant pale/eosinophilic cytoplasm, round basal nuclei, may have nucleoli) and outer/basal cuboidal cells (scant cytoplasm, flattened nuclei, inconspicuous)
─ Secretory cells: Cytoplasm contains PSA, PSAP; nuclei round, uniform, small nucleoli may be visible
─ Basal cells: Flattened, darker nuclei; form a continuous layer beneath secretory cells
─ Corpora amylacea: Eosinophilic, laminated concretions often present in glandular lumina, esp with age
─ Stroma: Smooth muscle and fibrous tissue
─ Central Zone (CZ) glands: More complex architecture (papillary infoldings, cribriforming), taller columnar cells with more crowded, pseudostratified, slightly larger, more hyperchromatic nuclei compared to PZ
Ancillary studies
─ Secretory cells IHC (+): PSA, PSAP, NKX3.1, Androgen Receptor (AR)
─ Basal cells IHC (+): p63, HMWCK (CK5/6, 34βE12), CK903
─ IHC (-): AMACR (racemase) is typically negative or weak/focal in benign glands
DDx
─ N/A for normal anatomy
Note
─ Two cell layers (secretory and basal) are hallmark of benign prostatic glands
─ Loss of basal cells is a key feature of prostatic adenocarcinoma
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Atrophy

Reduction in glandular volume and cytoplasmic content, often with nuclear crowding
Clinical
─ Common finding, increases with age; may be diffuse or focal; often associated with inflammation
Micro
─ Simple Atrophy: Small, crowded glands; scant basophilic cytoplasm (loss of eosinophilia); nuclei appear crowded, dark, pyknotic but bland; lobular or circumscribed clusters; stromal fibrosis common; basal cells present but may be compressed
─ Partial Atrophy (Clear Cell Atrophy): Crowded small to medium glands; clear to pale eosinophilic cytoplasm; nuclei may be enlarged, elongated, +/- small nucleoli; often merges with simple atrophy; less stromal fibrosis
─ Postatrophic Hyperplasia (PAH): Lobular proliferation of small, crowded, atrophic-appearing acini; cells with scant cytoplasm, enlarged, hyperchromatic nuclei, often prominent nucleoli esp if inflamed; basal cells present
Ancillary studies
─ Basal cells IHC (+): p63, HMWCK (CK5/6, 34βE12) confirm benignity
─ AMACR: Usually negative or weak/focal
DDx
─ Prostatic adenocarcinoma, Gleason pattern 3 (Lacks basal cells, infiltrative growth, prominent nucleoli, AMACR+)
─ Atypical Small Acinar Proliferation (ASAP) (Suspicious features but not diagnostic of cancer, often leads to repeat biopsy)
─ HGPIN (Larger glands, tufting, micropapillary patterns, prominent nucleoli)
Note
─ Nuclear changes in atrophy (esp PAH) can mimic malignancy; basal cell stains are crucial
─ Inflammation often accompanies atrophy
Media ─ placeholder ─ Post-atrophy hyperplasia (PAH) WSI

Hyperplasia (Benign Prostatic Hyperplasia - BPH / Nodular Hyperplasia)

Proliferation of both glandular and stromal elements, primarily in transition zone, leading to prostate enlargement
Clinical
─ Extremely common in older men; can cause lower urinary tract symptoms (LUTS)
Macro
─ Enlarged prostate; nodular cut surface, esp in transition zone; nodules can be rubbery (stromal) or spongy (glandular)
Micro
─ Nodular proliferation of glands and fibromuscular stroma
─ Glands: Variable size, often dilated, papillary infoldings, cystic changes common; lined by two cell layers (secretory and basal)
─ Stroma: Variable cellularity, smooth muscle and fibrous tissue
─ Specific Hyperplasia Patterns:
─ Basal Cell Hyperplasia: Proliferation of small, crowded glands lined predominantly by basal cells; may have solid nests; nuclei round +/- nucleolar prominence; luminal cytoplasm may be atrophic; can be atypical (streaming basal cells undermining secretory layer)
─ Clear Cell Cribriform Hyperplasia: Nodular proliferation of large cribriform glands in transition zone; lined by cells with clear-eosinophilic cytoplasm; small bland nuclei, prominent basal cell layer
Ancillary studies
─ Basal cells IHC (+): p63, HMWCK confirm benignity of glandular elements
DDx
─ Prostatic adenocarcinoma (Lacks basal cells, infiltrative growth, cytologic atypia)
─ HGPIN/Intraductal carcinoma (Occur in peripheral zone usually, distinct cytologic atypia, cribriform HGPIN has preserved basal cells but more atypia)
Note
─ BPH is a histologic diagnosis describing nodular hyperplasia
Media ─ placeholder ─ Basal cell hyperplasia of prostate H&E ─ Benign adenomatous and fibro-muscular hyperplasia H&E ─ Benign prostatic hyperplasia H&E ─ Benign prostatic hyperplasia and chronic inflammation H&E ─ Post-atrophy hyperplasia (PAH) WSI

Adenosis (Atypical Adenomatous Hyperplasia)

Localized proliferation of small, crowded, pale glands, often in transition zone as part of a hyperplastic nodule
Clinical
─ Incidental finding, usually in TURP or prostatectomy for BPH
Micro
─ Lobular proliferation of small to medium-sized, closely packed glands; glands often have pale or clear cytoplasm
─ Minimal cytologic atypia; nuclei round to oval, inconspicuous nucleoli; mitoses rare
─ Admixed poorly formed glands; basal cell layer is present, though may be attenuated
─ Stroma is usually scant between glands within the adenotic focus
Ancillary studies
─ Basal cells IHC (+): p63, HMWCK (may be patchy but present)
─ AMACR: Usually negative or weak/focal
DDx
─ Prostatic adenocarcinoma, Gleason pattern 3 (Lacks basal cells, infiltrative growth, prominent nucleoli, AMACR+)
─ Atrophy (Especially partial atrophy; adenosis glands are typically paler, more crowded, less stromal fibrosis)
Note
─ Considered a benign mimic of low-grade prostate cancer
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Sclerosing Adenosis

Variant of adenosis with prominent stromal cellularity and sclerosis, sometimes with a pseudoinfiltrative appearance
Clinical
─ Incidental finding
Micro
─ Lobular proliferation of small glands and nests embedded in a cellular, hyalinized, or sclerotic stroma
─ Glands may appear compressed or distorted by stroma; "streaming" or "Indian filing" of epithelial cells can occur
─ Epithelial cells are bland, may have small nucleoli; myoepithelial-like cells often prominent in stroma
─ Basal cell layer present around glands; hyaline sheaths around glands/nests may be seen
Ancillary studies
─ Basal cells IHC (+): p63, HMWCK
─ Myoepithelial cells in stroma IHC (+): SMA, S100 (variable)
DDx
─ Prostatic adenocarcinoma (Lacks basal cells, lacks myoepithelial stromal component)
─ Adenosis (Less stromal sclerosis and cellularity)
Note
─ Biphasic appearance (epithelial and myoepithelial/stromal) is characteristic
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Large & Cribriform Gland Patterns (Benign)

Includes benign entities that can form large or cribriform glands, potentially mimicking HGPIN or cribriform carcinoma
Micro
─ Central Zone (CZ) glands: Normal CZ histology shows complex, large glands with papillary infoldings and apparent cribriforming; nuclei are pseudostratified, slightly larger/darker than PZ
─ Clear Cell Cribriform Hyperplasia: (Described under Hyperplasia) Nodular, transition zone, clear cells, prominent basal layer
─ Verumontanum Mucosal Gland Hyperplasia (VMGH): Small, round, crowded glands near verumontanum/ejaculatory ducts; often with dark red concretions; basal cells present
─ Nephrogenic Adenoma: (Though typically bladder/urethra, can occur in prostatic urethra) Tubules, papillae, hobnail cells; thick basement membranes; colloid-like secretions; PAX8+, AMACR variable, basal cells absent
Ancillary studies
─ Basal cell markers (+ for benign prostatic patterns like CZ, CCC Hx, VMGH)
─ PAX8 (+ for Nephrogenic Adenoma)
DDx
─ HGPIN (Peripheral zone, cytologic atypia, prominent nucleoli, preserved basal cells)
─ Intraductal Carcinoma (Larger ducts, more severe atypia, often necrosis, preserved basal cells)
─ Prostatic adenocarcinoma, cribriform pattern (Invasive, lacks basal cells, significant atypia)
Note
─ Careful attention to location (CZ vs PZ vs TZ), cytology, and basal cell status is crucial
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Nonglandular Patterns (Benign)

Includes benign non-epithelial findings or reactive processes
Micro
─ Granulomatous Prostatitis: Granulomas (epithelioid histiocytes, lymphocytes, plasma cells, multinucleated giant cells); can be infectious (TB, fungal) or non-infectious (idiopathic, post-surgical, xanthogranulomatous)
─ Xanthogranulomatous Prostatitis: Sheets of foamy histiocytes, lymphocytes, plasma cells, foreign body giant cells
─ Non-specific Granulomatous Prostatitis: Most common; early phase with dilated ducts/acini, neutrophils, foamy histiocytes; late phase with dense chronic inflammation, fibrosis, destruction of glands
─ Prostatic Xanthoma: Collections of foamy histiocytes (lipid-laden macrophages) in stroma, not within glands; incidental finding
─ Paraganglion Tissue: Nests of chief cells (neuroendocrine markers+) and sustentacular cells (S100+) near prostate; incidental
─ Seminal Vesicle/Ejaculatory Duct Tissue: Complex glands lined by columnar cells with lipofuscin pigment, nuclear pleomorphism/hyperchromasia (degenerative atypia), surrounded by muscular wall; PSA/PSAP negative
─ Cowper's Glands: Lobulated mucinous glands in urogenital diaphragm area; dimorphic (central ducts, peripheral acini); mucin-rich cytoplasm; basal cells present; AMACR negative
─ Mesonephric Remnants: Small tubules/cords/ducts; cuboidal/columnar epithelium; bland nuclei; lack basal cells; GATA3+, PAX8+, CD10+, vimentin+; PSA/PSAP-, NKX3.1-, AMACR-
Ancillary studies
─ Specific stains for organisms if infectious granulomatous prostatitis suspected
─ Neuroendocrine markers for paraganglia
─ Basal cell markers for Cowper's glands
─ GATA3/PAX8 for mesonephric remnants
DDx
─ Depends on specific pattern:
─ Granulomatous prostatitis vs. high-grade cancer (esp. post-treatment)
─ Xanthoma vs. foamy gland carcinoma (Xanthoma is stromal, cancer is glandular, AMACR+)
─ Seminal vesicle vs. HGPIN/cancer (Lipofuscin, muscular wall, PSA/PSAP- in SV)
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Prostatitis

Granulomatous Prostatitis

Inflammation of prostate characterized by granulomas; can be infectious or non-infectious
Clinical
─ May present with LUTS, fever, tender prostate; PSA may be elevated
─ Infectious: e.g., tuberculosis (caseating granulomas, AFB+), fungal (specific organisms), post-BCG therapy
─ Non-infectious: Idiopathic (most common), post-surgical/biopsy, malakoplakia (rare in prostate), xanthogranulomatous
Micro
─ Non-specific Granulomatous Prostatitis: Most common; collections of epithelioid histiocytes, lymphocytes, plasma cells, multinucleated giant cells; often centered on ruptured ducts/acini; eosinophils may be present
─ Early phase: Dilated ducts/acini with neutrophils, foamy histiocytes
─ Late phase: Dense chronic inflammation, fibrosis, destruction of glands
─ Xanthogranulomatous Prostatitis: Sheets of foamy histiocytes, lymphocytes, plasma cells, foreign body giant cells; often associated with obstruction/necrosis
─ Tuberculous Prostatitis: Caseating granulomas with Langhans giant cells, epithelioid histiocytes, lymphocytes
─ Post-BCG Granulomas: Non-caseating granulomas after intravesical BCG therapy for bladder cancer
Ancillary studies
─ Special stains for organisms (AFB for TB, GMS/PAS for fungi) if infectious cause suspected
─ Serum PSA may be elevated
DDx
─ High-grade prostatic adenocarcinoma (esp. post-treatment changes or Gleason pattern 5 can mimic granulomatous reaction; IHC for PSA/PSAP and basal cell markers helpful)
─ Lymphoma (Monotonous lymphoid infiltrate, specific markers)
─ Malakoplakia (Michaelis-Gutmann bodies - rare in prostate)
Note
─ Important to exclude infectious etiology, especially tuberculosis in endemic areas or immunocompromised patients
─ Can be a diagnostic challenge on needle biopsy, mimicking cancer
Media ─ placeholder ─ Granulomatous prostatitis H&E ─ Granulomatous prostatitis WSI Acute Prostatitis

Acute inflammation of the prostate (Acute Prostatitis)

Clinical
─ Presents with fever, chills, malaise, dysuria, pelvic/perineal pain, tender prostate on DRE
─ Common uropathogens: E. coli, Klebsiella, Proteus, Enterococcus, Pseudomonas
─ Can lead to prostatic abscess, sepsis, or chronic prostatitis if inadequately treated
Macro
─ Prostate may be swollen, congested, tender
Micro
─ Predominantly neutrophilic infiltrate within and around prostatic acini and ducts
─ Stromal edema, vascular congestion, hemorrhage common
─ Microabscess formation (collections of neutrophils) may be present
─ Urothelium of prostatic urethra/ducts may show acute inflammation, ulceration
Ancillary studies
─ Urine culture and prostatic secretions culture often positive for bacteria
─ PSA may be markedly elevated
DDx
─ Chronic prostatitis (Predominantly lymphocytes/plasma cells, less neutrophils)
─ Granulomatous prostatitis (Presence of granulomas)
─ High-grade prostatic adenocarcinoma (Malignant glands, prominent nucleoli, lacks diffuse neutrophilic infiltrate)
Note
─ Requires prompt antibiotic therapy
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Chronic Prostatitis (Non-Granulomatous / Inflammatory CPPS)

Chronic inflammation of the prostate, which may be bacterial or non-bacterial (inflammatory chronic pelvic pain syndrome - CP/CPPS)
Clinical
─ Variable symptoms: Pelvic/perineal pain, LUTS (frequency, urgency, dysuria), painful ejaculation; may be asymptomatic
─ Chronic Bacterial Prostatitis (NIH Cat II): Recurrent UTIs with same pathogen, persistent prostatic infection
─ Inflammatory CP/CPPS (NIH Cat IIIA): Chronic pelvic pain, leukocytes in prostatic secretions/urine/semen, no demonstrable infection
Macro
─ Prostate may be normal, firm, or nodular
Micro
─ Chronic inflammatory infiltrate: Predominantly lymphocytes and plasma cells in stroma and around acini/ducts
─ Macrophages may be present; lymphoid aggregates or follicles (without well-formed germinal centers typically) can be seen
─ Glandular changes: Atrophy, ductal ectasia, epithelial hyperplasia or reactive atypia may be associated
─ Stromal fibrosis can occur with long-standing inflammation
─ Neutrophils are usually sparse or absent (unless acute exacerbation)
Ancillary studies
─ Prostatic secretions/EPS for leukocytes; cultures to distinguish bacterial from non-bacterial
─ PSA may be mildly elevated
DDx
─ Acute prostatitis (Predominance of neutrophils)
─ Granulomatous prostatitis (Presence of granulomas)
─ Lymphoma involving prostate (Monotonous atypical lymphoid infiltrate, specific markers)
─ Normal prostate with scattered lymphocytes (Inflammation is more prominent in chronic prostatitis)
Note
─ Histologic findings of chronic inflammation are common in prostate biopsies and may not always correlate with clinical symptoms of prostatitis
─ Treatment varies by subtype (antibiotics for bacterial, anti-inflammatory/alpha-blockers for CP/CPPS)
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Glandular neoplasms

Prostatic Cystadenoma

Rare benign cystic neoplasm of the prostate, composed of glands and cysts lined by prostatic-type epithelium, set in a bland fibromuscular stroma
Clinical
─ Adults, wide age range; may present with LUTS, hematuria, or be an incidental finding
─ Benign, does not recur or metastasize
Macro
─ Large, multicystic mass; cysts contain serous or hemorrhagic fluid
Micro
─ Multiloculated cystic lesion; cysts and glands lined by two cell layers (secretory and basal), similar to benign prostatic glands
─ Epithelium may be cuboidal, columnar, or flattened; may show papillary infoldings
─ Stroma is fibromuscular, bland, without atypia; may be abundant
─ No significant cytologic atypia, mitoses, or infiltrative growth
Ancillary studies
─ Secretory cells IHC (+): PSA, PSAP
─ Basal cells IHC (+): p63, HMWCK
DDx
─ Cystic BPH (Usually smaller, less complex, typical BPH nodules elsewhere)
─ Prostatic adenocarcinoma with cystic degeneration (Lacks basal cells, cytologic atypia of cancer)
─ MEST of kidney (If location is ambiguous, MEST has ovarian-type stroma, ER/PR+)
─ Seminal vesicle cysts (SV epithelium has lipofuscin, nuclear pleomorphism, PSA/PSAP-)
Note
─ Very rare tumor; essentially a benign cystic adenoma of prostatic glands
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High-Grade Prostatic Intraepithelial Neoplasia (HGPIN)

Proliferation of architecturally benign prostatic acini and/or ducts lined by cytologically atypical cells; considered a precursor to some prostatic adenocarcinomas
Clinical
─ Incidence increases with age; common finding in prostates with cancer; peripheral zone most common
─ Not a direct target for treatment, but indicates increased risk of concurrent or subsequent adenocarcinoma
Micro
─ Architecturally benign glands (pre-existing acini/ducts are preserved, no glandular crowding or infiltration)
─ Lined by crowded, pseudostratified epithelial cells with cytologic atypia: enlarged nuclei, prominent nucleoli (visible at 100-200x), hyperchromasia
─ Basal cell layer is present (though may be attenuated or focally disrupted)
─ Common patterns: Tufting (cellular mounds or tufts), micropapillary (short, filiform papillae without fibrovascular cores), cribriform (intraluminal epithelial bridging forming rounded spaces), flat (atypical cells lining glands without complex architecture)
─ Abrupt demarcation between atypical cells and adjacent benign epithelium may be seen
─ Mitoses uncommon; necrosis absent (if present, consider intraductal carcinoma)
Ancillary studies
─ Basal cells IHC (+): p63, HMWCK (confirms intraductal nature, distinguishes from invasive cribriform carcinoma)
─ AMACR IHC (+): Often positive in atypical cells (in >50% of HGPIN cases)
DDx
─ Intraductal carcinoma of the prostate (IDC-P) (More extensive cribriforming, solid intraductal growth, comedonecrosis, more severe cytologic atypia)
─ Prostatic adenocarcinoma, cribriform or Gleason pattern 4 (Invasive growth, lacks basal cells)
─ Reactive atypia/inflammation (Less nuclear atypia, prominent inflammation, nucleoli less prominent or more smudged)
─ Central zone glands (Normal CZ shows some complexity but lacks the distinct cytologic atypia of HGPIN)
Note
─ Diagnosis of HGPIN on biopsy warrants close follow-up due to increased cancer risk
─ Unusual PIN patterns: vacuolated/signet ring, mucinous, inverted (hobnail), small cell, foamy, squamous differentiation
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Intraductal Carcinoma of the Prostate (IDC-P)

Intraductal proliferation of malignant epithelial cells within pre-existing prostatic ducts and acini, characterized by significant architectural complexity and/or cytologic atypia, often associated with high-grade invasive carcinoma
Clinical
─ Strongly associated with high-grade (Gleason score ≥7), large volume invasive prostate cancer and poor prognosis
─ Rarely occurs as an isolated finding
Micro
─ Malignant epithelial cells filling and expanding prostatic ducts/acini; basal cell layer is present (at least focally)
─ Diagnostic patterns:
─ Solid: Ducts completely filled by sheets of neoplastic cells
─ Dense cribriform: Ducts filled with complex, fused glandular structures with small, slit-like lumina; >50% of lumen occluded
─ Loose cribriform/micropapillary: More delicate cribriform structures or micropapillae, but with marked nuclear atypia (nuclei ≥6x normal or non-neoplastic epithelial cell nucleus) OR comedonecrosis
─ Comedonecrosis: Central necrosis within ducts filled by neoplastic cells
─ Cytology: Marked nuclear pleomorphism, prominent nucleoli, frequent mitoses (often more severe than HGPIN)
Ancillary studies
─ Basal cells IHC (+): p63, HMWCK (confirms intraductal nature)
─ AMACR IHC (+): Usually strongly positive in neoplastic cells
─ ERG IHC (+): Often positive if associated ERG-fusion invasive cancer is present
DDx
─ HGPIN (Less architectural complexity, less cytologic atypia, no comedonecrosis, loose cribriform/micropapillary HGPIN lacks marked nuclear atypia)
─ Invasive cribriform adenocarcinoma (Lacks basal cell layer, shows stromal invasion)
─ Urothelial carcinoma involving prostatic ducts (GATA3+, p63+, PSA-, PSAP-)
Note
─ Presence of IDC-P on biopsy is an adverse prognostic indicator, even if invasive cancer is low grade
─ Represents spread of high-grade carcinoma into ducts or de novo intraductal origin
Media ─ placeholder ─ Intraductal carcinoma of the prostate H&E

Prostatic Acinar Adenocarcinoma

Malignant epithelial neoplasm originating from prostatic acini, characterized by infiltrative growth of glands lacking a basal cell layer
Clinical
─ Most common cancer in men (excluding skin); incidence increases with age; Black > White > Asian (healthcare disparity likely factor)
─ Risk factors: Age, family history (HOXB13, BRCA1/2, MMR genes, ATM, CHEK2), ?obesity; PSA screening controversial
─ Presentation: Elevated PSA, abnormal DRE, LUTS, bone pain (metastases); many are screen-detected
─ Prognosis depends on Gleason score/Grade Group, stage, PSA, surgical margins, perineural invasion, extraprostatic extension
Macro
─ Often ill-defined, firm, yellow-white areas, typically in peripheral zone; may be multifocal
Micro
─ Infiltrative growth of glands, often smaller than benign glands; loss of basal cell layer is a key feature
─ Cytology: Enlarged nuclei, prominent (often cherry-red) nucleoli; cytoplasm variable (pale, amphophilic, eosinophilic, foamy); straight, crisp luminal borders; minimal pleomorphism in typical low-grade cases
─ Architectural patterns (Gleason grading):
─ Pattern 3: Well-formed, discrete glands; infiltrative among benign glands; variable size/shape
─ Pattern 4: Poorly-formed/fused glands (glands sharing common walls, difficult to discern individual units); cribriform glands (rounded nests with multiple punched-out lumina); glomeruloid glands
─ Pattern 5: Sheets of cells, solid cords, single cells; comedonecrosis (central necrosis within sheets/cribriform structures)
─ Perineural invasion (tumor tracking along nerves), mucinous fibroplasia (stromal reaction), glomerulations common
Ancillary studies
─ Basal cell markers IHC (-): p63, HMWCK (CK5/6, 34βE12) (confirms absence of basal cells in malignant glands)
─ AMACR (racemase) IHC (+): Diffuse cytoplasmic staining in most adenocarcinomas (also + in HGPIN, some atrophy)
─ ERG IHC (+): Nuclear staining in ~50% cases (due to TMPRSS2-ERG fusion); specific but not sensitive
─ PSA, PSAP IHC (+): Confirm prostatic origin, esp in metastatic sites
Molecular
─ TMPRSS2-ERG fusion (~50%); PTEN loss (associated with progression); SPINK1 overexpression (ERG-negative subset); IDH1 mutations (rare)
─ Germline: HOXB13, BRCA1/2, ATM, CHEK2, MMR genes
─ Somatic: SPOP, FOXA1, TP53 (esp in high-grade/castration-resistant)
DDx
─ Benign mimics: Atrophy (esp PAH), adenosis, sclerosing adenosis, basal cell hyperplasia (all have basal cells)
─ HGPIN/IDC-P (Preserved basal cell layer, intraductal location)
─ Seminal vesicle epithelium (Lipofuscin, nuclear pleomorphism, muscular wall, PSA/PSAP-)
─ Urothelial carcinoma involving prostate (GATA3+, p63+, PSA/PSAP-)
Note
─ Gleason score (primary + secondary most common patterns) and Grade Group (1-5) are crucial for prognosis/management
─ Report % pattern 4/5; presence of cribriform/intraductal carcinoma
─ Cytologic features (e.g., prominent nucleoli) are important but grading is architectural
Media ─ placeholder ─ prostatic adenocarcinoma H&E

Prostatic Adenocarcinoma with Therapy Effect (Hormonal/Radiation)

Histologic changes in prostatic adenocarcinoma following androgen deprivation therapy (ADT) or radiation therapy
Clinical
─ Patients treated for prostate cancer with ADT (e.g., LHRH agonists, antiandrogens) or radiation (external beam or brachytherapy)
─ Aim of therapy is to induce tumor regression/cell death; histologic effects can persist
─ Post-treatment PSA levels monitored; rising PSA may indicate recurrence/resistance
Macro
─ Prostate may be smaller, firmer; tumor may be difficult to identify grossly
Micro
─ Hormonal Therapy Effect:
─ Tumor cells: Cytoplasmic clearing/vacuolization (may mimic clear cell carcinoma of other sites), shrunken eosinophilic cytoplasm, pyknotic nuclei, karyorrhexis
─ Glandular architecture: Atrophy of glands, reduced glandular complexity, glands may appear smaller, more spaced apart due to stromal fibrosis
─ Stroma: Increased stromal fibrosis, hyalinization; relative increase in stroma to gland ratio
─ Basal cells: Remain absent in treated cancer glands
─ Neuroendocrine differentiation: May become more prominent or induced
─ Radiation Therapy Effect:
─ Tumor cells: Nuclear atypia (enlargement, pleomorphism, hyperchromasia, smudged chromatin - "radiation atypia"), cytoplasmic vacuolization, bizarre cell forms; multinucleation
─ Glandular architecture: Glandular atrophy, distortion, loss of glands
─ Stroma: Fibrosis, hyalinization, atypical stromal fibroblasts (radiation fibroblasts - large, stellate, hyperchromatic), vascular changes (sclerosis, telangiectasias)
─ Squamous metaplasia: May occur in benign and malignant glands
─ Viable tumor: May be difficult to assess; look for glands with intact cytoplasm, recognizable nuclei, even if atypical; sheets or clusters of cells
Ancillary studies
─ IHC (-): Basal cell markers (p63, HMWCK) still absent in treated cancer glands
─ IHC (+): PSA, PSAP may be reduced in intensity but usually still positive in viable tumor cells
─ AMACR: May be reduced or lost in treated tumor cells
─ Ki-67: Usually low in effectively treated tumor
DDx
─ Benign prostatic glands with therapy effect (Will retain basal cells, though atypia can be significant)
─ High-grade prostatic intraepithelial neoplasia (HGPIN) with therapy effect (Retains basal cells, intraductal location)
─ Clear cell carcinoma (Primary or metastatic - different IHC profile, e.g., PAX8 for renal)
─ Granulomatous prostatitis (Post-radiation granulomas can occur)
Note
─ Distinguishing viable residual tumor from extensive therapy effect can be challenging
─ Reporting post-treatment changes should include assessment of residual tumor presence, extent, and Gleason score if possible (though grading can be difficult)
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Pseudohyperplastic Prostatic Adenocarcinoma

A variant of acinar adenocarcinoma characterized by large, branching, and dilated glands that closely mimic benign prostatic hyperplasia (BPH) or adenosis
Clinical
─ Typically found in transition zone, often incidentally in TURP specimens for BPH
─ PSA levels may be variable, sometimes not significantly elevated
─ Behavior generally similar to conventional acinar adenocarcinoma of comparable Gleason score (usually Gleason pattern 3)
Macro
─ May not be distinct from surrounding BPH nodules
Micro
─ Large, irregularly shaped, branching, and dilated glands resembling BPH; may have papillary infoldings or cribriform areas
─ Glands lined by a single layer of malignant cells (loss of basal cell layer)
─ Tumor cells: Cytoplasm often abundant, pale eosinophilic, or clear; nuclei usually show mild to moderate atypia (enlarged, hyperchromatic, prominent nucleoli may be less obvious than typical acinar cancer)
─ Mitotic figures rare
─ Often admixed with areas of conventional acinar adenocarcinoma
Ancillary studies
─ IHC (-): Basal cell markers (p63, HMWCK) are absent, confirming malignancy (crucial for diagnosis)
─ IHC (+): AMACR (usually diffuse and strong), PSA, PSAP
DDx
─ Benign prostatic hyperplasia (BPH) / Adenosis (Preserved basal cell layer, less cytologic atypia)
─ Clear cell cribriform hyperplasia (Benign, prominent basal cell layer, transition zone location)
─ Atrophy with cystic change (Preserved basal cells, atrophic cytologic features)
Note
─ Key diagnostic challenge is recognizing the subtle malignant features and confirming absence of basal cells
─ Usually corresponds to Gleason pattern 3
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Foamy Gland Adenocarcinoma

A variant of acinar adenocarcinoma characterized by glands lined by cells with abundant, foamy, xanthomatous-appearing cytoplasm
Clinical
─ Can occur at any age typical for prostate cancer; may be associated with slightly lower PSA levels for tumor volume
─ Behavior generally similar to conventional acinar adenocarcinoma of comparable Gleason score (usually Gleason pattern 3)
Macro
─ No specific gross features; may appear as typical adenocarcinoma
Micro
─ Infiltrative glands lined by a single layer of malignant cells (loss of basal cell layer)
─ Tumor cells: Abundant, foamy, or bubbly clear to pale eosinophilic cytoplasm, resembling histiocytes or clear cells of other sites
─ Nuclei: Often small, dark, pyknotic, and eccentrically placed (mimicking histiocytes); prominent nucleoli may be less apparent due to nuclear pyknosis but can be found
─ Glandular lumina may be inconspicuous or contain eosinophilic secretions
─ Often admixed with conventional acinar adenocarcinoma
Ancillary studies
─ IHC (-): Basal cell markers (p63, HMWCK) are absent
─ IHC (+): AMACR (usually diffuse and strong), PSA, PSAP (may be weaker than typical acinar)
─ IHC (-): CD68 (to distinguish from true histiocytes/xanthoma cells)
DDx
─ Prostatic xanthoma / Xanthogranulomatous prostatitis (Histiocytes are CD68+, stromal location for xanthoma, lack glandular formation, lack AMACR/PSA)
─ Clear cell RCC metastatic to prostate (PAX8+, CAIX+, PSA/PSAP-)
─ Signet ring cell carcinoma (Mucin+, distinct morphology)
─ Benign glands with clear cell change (e.g., partial atrophy) (Preserved basal cells)
Note
─ The bland, histiocyte-like appearance of nuclei can be a pitfall, leading to underdiagnosis
─ Usually corresponds to Gleason pattern 3
Media ─ placeholder ─ Adenocarcinoma, foamy gland variant, Gleason grade 5+5= score of 10 H&E

Prostatic Ductal Adenocarcinoma

An aggressive variant of prostate cancer characterized by tall, pseudostratified columnar cells forming complex papillary, cribriform, or glandular structures, often arising in large periurethral ducts but can occur in peripheral zone
Clinical
─ Older men, similar age to acinar adenocarcinoma; may present with hematuria, obstructive symptoms, or elevated PSA
─ Often admixed with acinar adenocarcinoma; pure ductal adenocarcinoma is rare
─ More aggressive than acinar adenocarcinoma of similar Gleason score; higher risk of extraprostatic extension, metastasis
Macro
─ May form exophytic, friable masses in prostatic urethra; or ill-defined infiltrative areas
Micro
─ Characterized by tall columnar cells, often with pseudostratification; cytoplasm typically amphophilic or eosinophilic
─ Architectural patterns:
─ Papillary: True fibrovascular cores lined by malignant cells (most common)
─ Cribriform: Large glands with intraluminal bridging, often with slit-like spaces
─ Glandular (endometrioid-like): Large glands resembling endometrial adenocarcinoma
─ Nuclei are typically high grade: enlarged, pleomorphic, hyperchromatic, prominent nucleoli
─ Mitotic figures often frequent; comedonecrosis may be present
─ Basal cells are absent in invasive areas
Ancillary studies
─ IHC (+): PSA, PSAP (may be weaker/patchier than acinar); AMACR; Androgen Receptor
─ IHC (-): Basal cell markers (p63, HMWCK) in invasive component
─ ERG: Can be positive if associated with ERG-fusion acinar cancer
DDx
─ Intraductal carcinoma of the prostate (IDC-P) (Preserved basal cell layer, confined to pre-existing ducts)
─ High-grade prostatic intraepithelial neoplasia (HGPIN) (Preserved basal cell layer, less architectural complexity/cytologic atypia than invasive ductal)
─ Urothelial carcinoma involving prostatic ducts/stroma (GATA3+, p63+, PSA/PSAP-)
─ Colorectal adenocarcinoma metastatic to prostate (CDX2+, CK20+, PSA/PSAP-)
Note
─ When admixed with acinar adenocarcinoma, it is graded based on its underlying architecture (e.g., cribriform ductal is Gleason pattern 4)
─ Pure ductal adenocarcinoma is considered high-grade
Media ─ placeholder ─ Prostatic ductal adenocarcinoma WSI ─ Prostatic ductal adenocarcinoma WSI WSI

Treatment-Related Neuroendocrine Prostate Cancer (NEPC)

Neuroendocrine differentiation arising in prostatic adenocarcinoma, usually after androgen deprivation therapy (ADT); can be focal or extensive (small cell or large cell neuroendocrine carcinoma)
Clinical
─ Patients with advanced prostate cancer treated with ADT; rising PSA may be absent despite progression (PSA-negative progression)
─ Aggressive clinical course, rapid progression, visceral metastases common; poor prognosis
Macro
─ May not have distinct gross features from treated acinar adenocarcinoma
Micro
─ Small Cell Neuroendocrine Carcinoma: Sheets, nests, trabeculae of small cells with scant cytoplasm, finely granular (salt-and-pepper) chromatin, nuclear molding, high mitotic rate, extensive necrosis
─ Large Cell Neuroendocrine Carcinoma: Large cells with more abundant cytoplasm, vesicular nuclei, prominent nucleoli, coarse chromatin, frequent mitoses, necrosis; organoid nesting, trabecular growth
─ Often admixed with residual treated acinar adenocarcinoma
Ancillary studies
─ Neuroendocrine markers IHC (+): Synaptophysin, Chromogranin A, CD56 (NCAM) (at least one, often multiple)
─ TTF1 IHC (+): Can be positive, esp in small cell component
─ PSA, PSAP IHC (- or weak/focal): In neuroendocrine component
─ Androgen Receptor IHC (- or low): In neuroendocrine component
─ Ki-67 IHC: High proliferation index
Molecular
─ Often associated with TP53 and RB1 loss/mutations; MYCN or AURKA amplification
DDx
─ High-grade acinar adenocarcinoma with neuroendocrine differentiation (focal NE markers, retains acinar morphology/AR expression)
─ Metastatic small cell carcinoma from lung or other sites (Clinical history, PAX8-, NKX3.1-)
─ Lymphoma/Leukemia (Hematopoietic markers+, PSA/PSAP-)
Note
─ Represents a form of lineage plasticity and treatment resistance
─ Pure NEPC is rare de novo; most are treatment-related
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Squamous Neoplasms

Adenosquamous Carcinoma of the Prostate

Rare malignant neoplasm with intimately admixed components of both prostatic adenocarcinoma (acinar or ductal) and squamous cell carcinoma
Clinical
─ Older men; de novo or after radiation/hormonal therapy for acinar adenocarcinoma
─ Aggressive, poor prognosis
Micro
─ Two distinct malignant components: each unequivocally malignant
─ Glandular: Typical acinar or ductal adenocarcinoma
─ Squamous: Infiltrating nests/sheets of polygonal cells with eosinophilic cytoplasm, intercellular bridges, keratinization (keratin pearls)
Ancillary studies
─ Glands IHC (+): PSA, PSAP
─ Squamous IHC (+): p63, HMWCK (CK5/6), CK14
DDx
─ Squamous metaplasia in benign prostate or acinar adenocarcinoma (Bland squamous cells, not infiltrative, often post-treatment/inflammation)
─ Urothelial carcinoma with squamous differentiation involving prostate (GATA3+, PSA/PSAP-)
─ Squamous cell carcinoma, pure (No glandular component)
Note
─ Both components are considered high-grade
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Squamous Cell Carcinoma (SCC) of the Prostate

Rare primary malignant neoplasm composed exclusively of squamous cells
Clinical
─ Older men; may arise after chronic inflammation, infection, radiation therapy, or hormonal therapy
─ Highly aggressive, poor prognosis; often presents at advanced stage
Micro
─ Infiltrating nests, sheets, or cords of malignant squamous cells
─ Characterized by intercellular bridges, keratinization (individual cell or keratin pearls), eosinophilic cytoplasm
─ Nuclear atypia, pleomorphism, mitoses usually prominent
─ No glandular component present (by definition)
Ancillary studies
─ IHC (+): p63, HMWCK (CK5/6), CK14, EMA
─ IHC (-): PSA, PSAP, GATA3 (to exclude urothelial)
DDx
─ Urothelial carcinoma with extensive squamous differentiation involving prostate (GATA3+)
─ Metastatic SCC from another site (Clinical history, imaging)
─ Adenosquamous carcinoma (Presence of glandular component)
Note
─ Diagnosis of primary prostatic SCC requires exclusion of origin from bladder/urethra or metastasis
Media ─ placeholder ─ squamous cell carcinoma H&E

Adenoid Cystic (Basal Cell) Carcinoma of the Prostate

Rare malignant neoplasm resembling adenoid cystic carcinoma of salivary glands, thought to be of basal cell origin
Clinical
─ older men, indolent in most, can recur locally
Micro
─ Infiltrative nests/cords of basaloid cells with scant cytoplasm and hyperchromatic nuclei
─ Characteristic patterns: cribriform, tubular, and solid
─ In cribriform pattern, lumens contain PAS+ hyaline material or mucoid secretions
─ Perineural invasion common; mitoses infrequent
Ancillary studies
─ IHC (+): p63, HMWCK (CK5/6), CK7 (often), Bcl-2
─ IHC (-): PSA, PSAP (or very focal), AMACR, Androgen Receptor (usually)
─ c-Kit (CD117): Variable, often positive
Molecular
─ MYB rearrangements (similar to salivary gland ACC)
DDx
─ Basal cell hyperplasia (Lobular, circumscribed, less atypia, lacks true cribriforming with hyaline material)
─ Urothelial carcinoma with nesting/microcystic features (GATA3+, p63+, PSA/PSAP-)
─ Acinar adenocarcinoma, Gleason pattern 4 cribriform (PSA+, AMACR+, lacks biphasic pattern with hyaline material)
Note
─ Term "basal cell carcinoma" is also used, but "adenoid cystic carcinoma" emphasizes the specific morphology
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Prostatic Stromal Tumor of Uncertain Malignant Potential (STUMP)

A rare prostatic stromal proliferation characterized by cellularity and/or cytologic atypia that is insufficient for a diagnosis of stromal sarcoma, but which exceeds that of benign stromal hyperplasia/nodules
Clinical
─ Adult men; LUTS, hematuria, or incidental finding
─ Behavior uncertain; most indolent, some may recur locally or rarely progress
Micro
─ Cellular stromal proliferation, phyllodes-like pattern or a more patternless growth
─ Stromal cells are spindle to stellate, variable amounts of eosinophilic to clear cytoplasm
─ Cytologic atypia mild to moderat; mitotic activity usually low
─ Absent or minimal degenerative changes, myxoid stroma, hemorrhage, or necrosis
─ Benign prostatic glands entrapped or admixed within the stromal proliferation
Ancillary studies
─ IHC (+): CD34 (variable), PR, Estrogen receptor (ER, variable), Desmin (variable), Actin (variable)
─ IHC (-): Cytokeratins (except in entrapped glands), S100, PSA
DDx
─ BPH with stromal predominance (Less cellular, bland cytology, no atypia)
─ Prostatic stromal sarcoma (marked atypia, higher mitotic rate, infiltrative growth, necrosis)
─ Solitary fibrous tumor (STAT6+,storiform, hemangiopericytoma-like vessels)
─ Leiomyoma/Leiomyosarcoma (prominent smooth muscle differentiation)
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Prostatic Stromal Sarcoma

Rare malignant mesenchymal neoplasm arising from prostatic stroma, characterized by significant cellularity, cytologic atypia, mitotic activity, and infiltrative growth
Clinical
─ Adult men; obstructive symptoms, pelvic mass, or pain
─ Aggressive with local recurrence and distant metastases
Micro
─ Highly cellular spindle cell proliferation; fascicular, storiform, herringbone; infiltrative
─ Cytologic atypia: pleomorphism, hyperchromasia, irregular contours, prominent nucleoli
─ Mitotic activity high
─ Necrosis common; hemorrhage may be seen
─ May show heterologous differentiation (e.g., rhabdomyosarcomatous, chondrosarcomatous - rare)
─ Overgrowth of stromal component relative to benign epithelial elements
Ancillary studies
─ IHC (+): Vimentin, CD34 (variable), PR (often lost or reduced vs STUMP), Desmin (variable), Actin (variable)
─ IHC (-): Cytokeratins (except entrapped benign glands), S100, PSA
─ Ki-67 IHC: High proliferation index
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Testis

Germ Cell Tumors

Germ Cell Neoplasia In Situ (GCNIS)

Precursor lesion for most testicular germ cell tumors (TGCTs) of post-pubertal type; characterized by atypical germ cells within seminiferous tubules
Clinical
─ typically found in adults, found incidentally adjacent to TGCT, or in infertile men, cryptorchidism
─ High risk of progression to invasive TGCT (seminoma or nonseminoma) within if untreated
Micro
─ Seminiferous tubules lined by atypical germ cells (gonocyte-like); tubules maintain normal diameter
─ Atypical cells: Large, round to polygonal, clear or pale eosinophilic cytoplasm (glycogen-rich), large vesicular nuclei, prominent nucleoli, distinct cell membranes; located along basement membrane, replacing normal spermatogenic epithelium
─ Sertoli cells present, often compressed; spermatogenesis absent or reduced in affected tubules
─ No invasion
Ancillary studies
─ IHC (+): PLAP, OCT3/4, SALL4, D2-40, CD117
─ IHC (-): Cytokeratins, SOX17
DDx
─ Normal prepubertal testis (Gonocytes are normal, OCT3/4+, PLAP+)
─ Spermatocytic tumor (Older men, intratubular spread has different morphology, OCT3/4-)
─ Seminoma, intratubular spread (Cells fill and expand tubules, pleomorphic)
─ Embryonal carcinoma, intratubular spread (pleomorphic, cytokeratin+)
Note
─ Formerly known as intratubular germ cell neoplasia, unclassified (IGCNU)
─ "Intratubular seminoma" refers to GCNIS where neoplastic cells completely fill tubules, resembling seminoma but confined
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Seminoma

Malignant germ cell tumor composed of uniform cells resembling primordial germ cells/gonocytes, typically with a prominent lymphocytic infiltrate
Clinical
─ Testis; most common pure TGCT, peak incidence in 30-40s
─ Excellent prognosis, highly sensitive to radiotherapy and chemotherapy; presents as testicular mass
─ Serum hCG may be mildly elevated due to syncytiotrophoblastic cells (in ~10-15%); LDH often elevated
Macro
─ Well-circumscribed, lobulated, homogeneous, tan-white or cream-colored, fleshy cut surface; may bulge
─ Necrosis or hemorrhage uncommon unless large
Micro
─ Diffuse sheets, nests, or lobules of uniform tumor cells separated by delicate fibrous septa containing a prominent lymphocytic infiltrate (mostly T-cells)
─ Tumor cells: Large, round to polygonal, distinct cell membranes, clear or pale eosinophilic cytoplasm (glycogen-rich), centrally located large vesicular nucleus with 1-2 prominent nucleoli
─ Mitotic figures variable; granulomatous reaction common
─ Syncytiotrophoblastic giant cells (STGCs) may be present focally (source of hCG)
Ancillary studies
─ IHC (+): OCT3/4 (nuclear), SALL4 (nuclear), PLAP, c-KIT (CD117), D2-40 (membranous)
─ IHC (-): Cytokeratins (AE1/AE3, CAM5.2 - except rare perinuclear dots), CD30, SOX2, AFP, Glypican-3 (except STGCs for hCG)
─ Molecular: Isochromosome 12p (i12p) common to most post-pubertal TGCTs; KIT mutations can occur
DDx
─ Embryonal carcinoma (More pleomorphic, cohesive sheets/glands/papillae, cytokeratin+, CD30+, OCT3/4+, SALL4+)
─ Spermatocytic tumor (Older men, trimorphic population, OCT3/4-, PLAP-, c-KIT variable)
─ Lymphoma (Older men, diffuse infiltrate, hematopoietic markers+, OCT3/4-)
─ Yolk sac tumor, solid pattern (Reticular/microcystic areas elsewhere, AFP+, Glypican-3+)
Note
─ Ovarian equivalent is dysgerminoma; CNS equivalent is germinoma
Media ─ placeholder ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma H&E ─ Seminoma WSI ─ Seminoma WSI ─ seminoma H&E

Embryonal Carcinoma (EC)

Malignant germ cell tumor composed of primitive-appearing epithelial cells with marked pleomorphism, capable of somatic and extraembryonic differentiation
Clinical
─ Testis; peak incidence in 20-30s; often a component of mixed GCTs
─ Aggressive tumor with early hematogenous and lymphatic spread; presents as testicular mass
─ Serum AFP and/or hCG may be elevated (hCG if STGCs present, AFP if admixed YST or hepatoid differentiation)
Macro
─ Poorly circumscribed, variegated cut surface with hemorrhage and necrosis common; grayish-white, fleshy
Micro
─ Highly pleomorphic cells arranged in various patterns: solid sheets, nests, tubules/glands, papillary structures; indistinct cell borders, overlapping nuclei
─ Tumor cells: Large, anaplastic, vesicular or hyperchromatic nuclei, prominent irregular nucleoli, amphophilic or basophilic cytoplasm
─ High mitotic activity, frequent apoptosis; vascular invasion common
─ May show primitive somatic differentiation (e.g., neural, rhabdomyoblastic) or STGCs
Ancillary studies
─ IHC (+): OCT3/4 (nuclear), SALL4 (nuclear), SOX2 (nuclear), CD30 (membranous), Cytokeratins (AE1/AE3, CAM5.2, CK7 variable)
─ IHC (-): c-KIT (CD117, usually), PLAP (often weaker or negative compared to seminoma), Glypican-3 (unless YST component), D2-40
─ Molecular: i12p common
DDx
─ Seminoma (Less pleomorphic, clear cytoplasm, lymphocytic infiltrate, OCT3/4+, CD30-, CK-)
─ Yolk sac tumor (Reticular, microcystic, Schiller-Duval bodies, AFP+, Glypican-3+, SALL4+, OCT3/4 variable)
─ Choriocarcinoma (Biphasic pattern of cytotrophoblasts and syncytiotrophoblasts, extensive hemorrhage, hCG++)
─ Poorly differentiated somatic carcinoma (e.g., metastatic) (Clinical history, different IHC profile)
Note
─ Considered the totipotential stem cell of nonseminomatous GCTs
Media ─ placeholder ─ Embryonal carcinoma + choriocarcinoma WSI ─ Embryonal carcinoma testis H&E ─ Embryonal carcinoma, mimic seminoma H&E

Choriocarcinoma

Highly malignant germ cell tumor composed of neoplastic cytotrophoblasts and syncytiotrophoblasts, recapitulating placental villous trophoblast
Clinical
─ Testis; rare as a pure tumor (<1%), more common as a component of mixed GCTs; peak incidence 20-30s
─ Extremely aggressive with widespread early hematogenous metastases (esp lung, liver, brain); presents as small testicular nodule or with symptoms of metastases
─ Serum hCG markedly elevated (produced by syncytiotrophoblasts)
Macro
─ Typically small, hemorrhagic, and necrotic mass; may not be palpable if extensively metastatic ("burned-out" primary)
Micro
─ Biphasic pattern:
─ Cytotrophoblasts: Polygonal cells with clear cytoplasm, distinct cell borders, single nucleus; arranged in sheets or cords
─ Syncytiotrophoblasts: Large, multinucleated giant cells with dense eosinophilic or amphophilic cytoplasm, smudged hyperchromatic nuclei; often cap cytotrophoblastic elements or line vascular spaces
─ Extensive hemorrhage and necrosis are characteristic; vascular invasion is prominent
─ No formation of chorionic villi
Ancillary studies
─ Syncytiotrophoblasts IHC (+): hCG (strong diffuse), inhibin, Glypican-3, SALL4
─ Cytotrophoblasts IHC (+): p63 (often), GATA3, SALL4, CK7 (variable), EMA (variable)
─ OCT3/4 IHC (- or focal in cytotrophoblasts)
─ Molecular: i12p common
DDx
─ Seminoma or Embryonal Carcinoma with scattered syncytiotrophoblastic cells (Lacks biphasic pattern of choriocarcinoma, hCG elevation less marked)
─ Yolk sac tumor with syncytiotrophoblastic cells (YST morphology elsewhere, AFP+)
─ Metastatic carcinoma with trophoblastic differentiation (Rare, clinical history)
Note
─ Pure choriocarcinoma in testis is very rare and has a very poor prognosis
─ Presence of any choriocarcinoma component in a mixed GCT worsens prognosis
Media ─ placeholder ─ Choriocarcinoma / seminoma H&E ─ Embryonal carcinoma + choriocarcinoma WSI

Yolk Sac Tumor (YST), Postpubertal-Type

A malignant germ cell tumor recapitulating extraembryonic yolk sac, endodermal sinuses, and/or primitive gut epithelium
Clinical
─ Testis; most common GCT in infants/young children (prepubertal-type, different entity); in adults, usually a component of mixed GCTs, pure form rare; peak 20-30s for postpubertal
─ Serum AFP is characteristically elevated; presents as testicular mass
Macro
─ Often poorly circumscribed; grayish-white or yellow-tan, soft, gelatinous, or mucoid; cystic areas, hemorrhage, necrosis common
Micro
─ Highly variable histology; common patterns:
─ Microcystic/Reticular: Anastomosing cords and spaces lined by flattened to cuboidal cells
─ Schiller-Duval bodies: Pathognomonic; papillary structure with a central vessel lined by tumor cells, projecting into a cystic space (endodermal sinus-like)
─ Solid: Sheets of polygonal cells with clear to eosinophilic cytoplasm
─ Glandular/Alveolar: Forming glands or acini
─ Papillary: Papillary fronds
─ Hepatoid: Sheets of large polygonal cells with eosinophilic cytoplasm resembling hepatocytes
─ Parietal: Extracellular hyaline/basement membrane material deposition
─ Hyaline globules (intracytoplasmic or extracellular, PAS-D positive, AFP-positive) are characteristic
─ Tumor cells: Cuboidal, columnar, flattened, or polygonal; nuclei variable, often vesicular with prominent nucleoli
Ancillary studies
─ IHC (+): AFP (alpha-fetoprotein, often strong), Glypican-3 (strong diffuse), SALL4 (nuclear), Cytokeratins (AE1/AE3, CAM5.2)
─ IHC (Variable/Focal): OCT3/4 (can be focal/weak, esp in less differentiated areas), CDX2 (in glandular areas)
─ IHC (-): CD30 (usually), SOX2 (usually), c-KIT (usually)
─ Molecular: i12p common in postpubertal type
DDx
─ Seminoma (Clear cells, lymphocytic infiltrate, OCT3/4+, AFP-, Glypican-3-)
─ Embryonal carcinoma (More pleomorphic, CD30+, SOX2+, AFP usually negative unless YST component)
─ Sertoli cell tumor (Tubular patterns, but cells are bland, inhibin+, SF1+, AFP-)
─ Clear cell carcinoma of Mullerian type (Rare in testis, PAX8+, different morphology)
Note
─ Prepubertal YST has excellent prognosis; postpubertal YST (especially pure) is more aggressive
─ Most common component associated with teratoma in mixed GCTs
Media ─ placeholder ─ Yolk sac / embryonal carcinoma WSI ─ Yolk sac tumour H&E ─ Yolk sac tumour, testis H&E ─ Yolk sac tumour>90% and malignant teratoma undifferntiated (MTU <10%) H&E

Teratoma, Postpubertal-Type

A germ cell tumor composed of tissues derived from two or more germ cell layers (ectoderm, mesoderm, endoderm), exhibiting various degrees of differentiation
Clinical
─ Testis; in postpubertal males, all teratomas are considered malignant (capable of metastasis, regardless of histologic maturity)
─ Often a component of mixed GCTs; pure teratoma is less common
─ Serum tumor markers (AFP, hCG) usually normal unless other GCT components are present
Macro
─ Typically multicystic, heterogeneous mass; may contain cartilage, bone, hair, sebaceous material; solid areas may be present
Micro
─ Wide variety of differentiated (mature) or undifferentiated (immature) tissues:
─ Mature: Squamous epithelium (cysts, keratin), glandular epithelium (intestinal, respiratory), cartilage, bone, adipose tissue, smooth muscle, neural tissue (glia, ganglion cells)
─ Immature: Primitive neuroectoderm (rosettes, tubules), immature mesenchyme, primitive endodermal or ectodermal structures
─ Somatic-type malignancy: Carcinoma (squamous, adeno), sarcoma (rhabdo, chondro), or PNET can arise within a teratoma (rare, worsens prognosis)
Ancillary studies
─ IHC depends on tissue types present (e.g., S100 for neural, CK for epithelial, desmin for muscle)
─ Germ cell markers (OCT3/4, SALL4) are negative in differentiated teratomatous elements but may be positive in adjacent GCNIS or other GCT components
─ Molecular: i12p common in postpubertal type
DDx
─ Epidermoid/Dermoid cyst (Benign, only mature squamous epithelium and adnexal structures, no other germ layers, prepubertal or postpubertal)
─ Yolk sac tumor (May have glandular or hepatoid areas, but AFP+, Glypican-3+)
─ Mixed GCT (If other components like EC, YST, seminoma, chorio are present)
Note
─ Unlike ovarian teratomas, postpubertal testicular teratomas (even if histologically mature) can metastasize (metastases may be teratoma or other GCT elements)
─ "Mature teratoma" and "immature teratoma" terms still used, but both considered malignant in postpubertal males
Media ─ placeholder ─ Testicular teratoma H&E

Mixed Germ Cell Tumor (Mixed GCT)

A testicular germ cell tumor composed of more than one GCT component (e.g., seminoma, embryonal carcinoma, yolk sac tumor, teratoma, choriocarcinoma)
Clinical
─ Testis; common presentation of nonseminomatous GCTs; peak incidence 20-30s
─ Clinical behavior and prognosis depend on the types and proportions of components, and presence of lymphovascular invasion
─ Serum tumor markers (AFP, hCG, LDH) often elevated, pattern depends on components
Macro
─ Heterogeneous, variegated appearance; often large with areas of hemorrhage, necrosis, cystic change reflecting different components
Micro
─ Two or more distinct GCT histologies present; common combinations include EC+YST, EC+Teratoma, EC+YST+Teratoma, Seminoma+EC
─ Each component should be identified and its percentage estimated
─ GCNIS is usually present in adjacent parenchyma
Ancillary studies
─ IHC panel targeting different components is crucial: OCT3/4, SALL4, PLAP, c-KIT, D2-40 (for seminoma); CD30, SOX2, CKs (for EC); AFP, Glypican-3 (for YST); hCG, p63 (for chorio); specific markers for teratomatous elements
DDx
─ Pure GCT (Only one histologic type present)
─ Regressed GCT (Predominantly scar with minimal or no viable tumor)
Note
─ Most common type of nonseminomatous GCT
─ Report approximate percentage of each component; presence of choriocarcinoma or extensive EC (>50%) or lymphovascular invasion indicates worse prognosis
─ Syncytiotrophoblasts alone do not constitute choriocarcinoma component
Media ─ placeholder ─ Mixed germ cell tumour H&E ─ Mixed germ cell tumour H&E ─ Mixed germ cell tumour (Teratoma intermediate with yolk sac tumour) H&E H&E ─ Mixed germ cell tumour (embryonal carcinoma, yolk sac tumour, teratoma) H&E ─ Mixed germ cell tumour (embryonal carcinoma/seminoma) H&E ─ Mixed germ cell tumour (predominantly choriocarcinoma with a single focus of embryonal carcinoma) H&E ─ Mixed germ cell tumour of testis H&E ─ Mixed germ cell tumour, including teratoma differentiated and classical seminoma H&E ─ Mixed germ cell tumour: Embryonal carcinoma + Seminoma H&E ─ Mixed non-seminomatous germ cell tumour H&E ─ Mixed seminomatous and no-seminomatous germ cell tumour H&E ─ Mixed seminomatous germ cell tumour H&E ─ Nonseminomatous germ cell tumour - mixed embryonal carcinoma / teratoma H&E

Regressed Germ Cell Tumor ("Burned-Out" Germ Cell Tumor)

Testicular scar or fibrotic nodule representing spontaneous and extensive regression of a GCT, often presenting with metastases
Clinical
─ Testis; patients may present with symptoms of metastatic GCT (e.g., retroperitoneal mass, lung nodules) with a small, impalpable, or normal-feeling testis, or a testicular scar
─ Serum markers may be elevated depending on metastatic components
Macro
─ Testis may be normal size or atrophic; a discrete, firm, white-gray scar or fibrotic nodule, often with calcification
Micro
─ Central scar: Dense hyalinized fibrous tissue, often with coarse calcifications (hematoxyphilic bodies), hemosiderin deposition, lymphoplasmacytic infiltrate
─ Evidence of prior GCT:
─ GCNIS in adjacent tubules (common)
─ Tubular atrophy and microlithiasis
─ Clusters of atypical cells or ghost outlines of tumor cells within the scar (rare)
─ Lymphovascular invasion by GCT elements may be seen at periphery of scar
─ Viable tumor is often minimal or absent in the testicular primary
Ancillary studies
─ IHC for GCT markers may highlight rare residual cells or GCNIS if present
DDx
─ Testicular atrophy/fibrosis due to other causes (e.g., ischemia, inflammation, trauma) (Lack of GCNIS, specific calcifications, or history suggestive of GCT)
─ Sclerosing Sertoli cell tumor (Rare, different morphology if viable tumor present)
Note
─ Important diagnosis as it explains metastatic GCT with an occult or absent testicular primary
─ Thorough sampling of any testicular scar in context of metastatic GCT is crucial
Media ─ placeholder ─ Scanty germ cell tumour (embryonal carcinoma) showing signs of regression WSI

Spermatocytic Tumor

A rare germ cell neoplasm of the testis, typically occurring in older men, composed of a polymorphous population of cells at different stages of maturation
Clinical
─ Testis; older men (mean age 50-60s, rarely <30 years)
─ Slow-growing, painless testicular mass; excellent prognosis, metastases are exceptionally rare (anaplastic variant has higher risk)
─ Not associated with GCNIS, cryptorchidism, or other GCT types; serum tumor markers (AFP, hCG) are negative
Macro
─ Well-circumscribed, soft, fleshy, tan-gray or yellowish, often mucoid or gelatinous; may be multicystic
Micro
─ Polymorphous population of tumor cells arranged in sheets, nests, or nodules; stroma is often edematous or myxoid
─ Three main cell types:
1. Small lymphocyte-like cells: Scant cytoplasm, round dark nuclei (6-8 µm)
2. Intermediate-sized cells: Most common; round eosinophilic cytoplasm, round nucleus with coarse, clumped, or spireme-like chromatin (15-20 µm)
3. Large cells (giant cells): Round to multinucleated, similar nuclear features (up to 50-100 µm)
─ Mitotic figures are usually present; intercellular bridges may be seen
─ No lymphocytic infiltrate, granulomas, or vascular invasion typically
─ Anaplastic variant: Sarcomatoid appearance with pleomorphism, increased mitoses, necrosis (rare, more aggressive)
Ancillary studies
─ IHC (+): SALL4 (nuclear, often strong), CD117 (c-KIT, variable), VASA (variable), NY-ESO-1 (variable)
─ IHC (-): OCT3/4, PLAP, AFP, hCG, SOX2, CD30, Cytokeratins, EMA, D2-40
─ Molecular: No i12p; gains of chromosome 9 common
DDx
─ Seminoma (Younger patients, uniform cells, lymphocytic infiltrate, OCT3/4+, PLAP+)
─ Lymphoma (Older men, diffuse infiltrate of atypical lymphoid cells, hematopoietic markers+)
─ Embryonal carcinoma (Younger patients, pleomorphic epithelial cells, OCT3/4+, CD30+, CK+)
Note
─ Formerly known as spermatocytic seminoma, but it's a distinct entity from classic seminoma
─ Does not arise from GCNIS and is not part of the usual i12p-driven GCT family
Media ─ placeholder ─ Spermatocytic tumour H&E

Teratoma & Yolk Sac Tumor, Prepubertal-Type

Benign germ cell tumors of infants and young children, distinct from their postpubertal counterparts; prepubertal teratomas are almost always mature and benign, and prepubertal YSTs have an excellent prognosis
Clinical
─ Testis; infants and young children (usually <4 years old)
─ Teratoma: Usually presents as painless testicular mass; benign, no metastatic potential
─ Yolk Sac Tumor: Most common testicular tumor in this age group; presents as painless mass, AFP markedly elevated; excellent prognosis with surgery (+/- chemotherapy for advanced stage)
Macro
─ Teratoma: Often cystic, may contain cartilage, bone, sebaceous material
─ Yolk Sac Tumor: Solid, grayish-yellow, often gelatinous or mucoid
Micro
─ Teratoma, Prepubertal-Type: Composed entirely of mature tissues from ectoderm, mesoderm, and endoderm (e.g., squamous epithelium, glands, cartilage, neural tissue); no immature elements, no GCNIS, no other GCT components
─ Yolk Sac Tumor, Prepubertal-Type: Similar histology to postpubertal YST (microcystic, reticular, Schiller-Duval bodies, hyaline globules) but occurs in a prepubertal testis, lacks GCNIS, and is not associated with i12p
Ancillary studies
─ Teratoma: IHC depends on tissue types; germ cell markers negative in mature elements
─ Yolk Sac Tumor: IHC (+) AFP, Glypican-3, SALL4, Cytokeratins; IHC (-) OCT3/4 (or very focal)
─ Molecular: Lack i12p; different molecular pathogenesis from postpubertal GCTs
DDx
─ Postpubertal teratoma/YST (Older age, associated GCNIS, i12p+, postpubertal teratoma considered malignant)
─ Epidermoid cyst (Only mature squamous epithelium and keratin, no other germ layers)
─ Juvenile granulosa cell tumor (Cystic, follicular structures, inhibin+)
Note
─ These are considered separate entities from their postpubertal counterparts due to different biology and clinical behavior
─ Prepubertal teratoma is benign; prepubertal YST has excellent prognosis
Media ─ placeholder ─

Sex Cord Stromal Tumors

Adult Granulosa Cell Tumor

Rare sex cord-stromal tumor resembling ovarian granulosa cell tumor, occurring in adult males
Clinical
─ Testis; adult men (wide age range, mean 40-50s)
─ May present as testicular mass; can be hormonally active (estrogen production leading to gynecomastia, decreased libido; rarely androgenic)
─ Behavior is variable; most are benign, but ~10-20% can recur or metastasize late
Macro
─ Usually well-circumscribed, solid, firm; yellow-tan to white; cystic areas or hemorrhage may be present
Micro
─ Various patterns:
─ Microfollicular: Small, round, gland-like spaces filled with eosinophilic material (Call-Exner bodies - pathognomonic if present)
─ Macrofollicular: Larger cystic spaces
─ Trabecular/insular: Cords or nests of tumor cells
─ Diffuse/Solid: Sheets of cells
─ Tumor cells: Uniform, polygonal to spindle, scant eosinophilic cytoplasm; characteristic "coffee-bean" grooved nuclei (longitudinally grooved)
─ Mitotic activity usually low; nuclear atypia mild
Ancillary studies
─ IHC (+): Inhibin-alpha (cytoplasmic/membranous), Calretinin (nuclear/cytoplasmic), SF-1 (Steroidogenic Factor 1, nuclear), FOXL2 (nuclear, specific), Vimentin, WT1 (nuclear), SMA (variable)
─ IHC (-): EMA, PLAP, OCT3/4, SALL4, Chromogranin, Synaptophysin
─ Molecular: FOXL2 (C134W/402C>G) mutation is characteristic (as in ovarian adult granulosa cell tumor)
DDx
─ Sertoli cell tumor (Often tubular, lacks nuclear grooves/Call-Exner bodies, FOXL2-)
─ Seminoma (OCT3/4+, PLAP+, clear cytoplasm, lymphocytic infiltrate, FOXL2-)
─ Lymphoma (Hematopoietic markers+, FOXL2-)
─ Yolk sac tumor (AFP+, Glypican-3+, different morphology, FOXL2-)
Note
─ Testicular counterpart of ovarian adult granulosa cell tumor
─ Late recurrences can occur, so long-term follow-up is recommended
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Juvenile Granulosa Cell Tumor

Rare benign sex cord-stromal tumor, almost exclusively occurring in infants, distinct from adult granulosa cell tumor
Clinical
─ Testis; infants (usually <6 months old), rarely in older children or adults
─ Presents as testicular mass, often associated with testicular anomalies (e.g., cryptorchidism, ambiguous genitalia); may cause isosexual precocity due to hormone production
─ Benign, excellent prognosis; metastases do not occur
Macro
─ Well-circumscribed, often multicystic; yellow-tan to gray; cysts contain watery or mucoid fluid
Micro
─ Predominantly macrofollicular pattern: Large, variably sized follicles filled with eosinophilic or basophilic fluid
─ Follicles lined by granulosa cells and theca-like cells; granulosa cells are plump, round to cuboidal, with eosinophilic cytoplasm
─ Nuclei are round, non-grooved (unlike adult type), often vesicular with prominent nucleoli; mitotic figures may be present but atypia is minimal
─ Call-Exner bodies are absent
─ Stroma between follicles may be edematous or cellular (theca-like cells)
Ancillary studies
─ IHC (+): Inhibin-alpha, Calretinin, SF-1, Vimentin, WT1 (variable)
─ IHC (-): FOXL2 (no FOXL2 mutation), PLAP, OCT3/4, SALL4
DDx
─ Yolk sac tumor, cystic variant (AFP+, Glypican-3+, different cytology)
─ Teratoma, cystic (Multiple germ layer differentiation)
─ Cystic dysplasia of the rete testis (Benign cystic dilation, not a true neoplasm)
Note
─ Most common testicular tumor in the first 6 months of life
─ Distinguished from adult granulosa cell tumor by age, macrofollicular pattern, lack of nuclear grooves, and absence of FOXL2 mutation
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Leydig Cell Tumor

A sex cord-stromal tumor composed of cells resembling normal Leydig cells, capable of androgen and/or estrogen production
Clinical
─ Testis; bimodal age distribution: prepubertal boys (5-10 years, often with isosexual precocity) and adults (30-60 years, may have gynecomastia, decreased libido, or be asymptomatic)
─ Most common pure sex cord-stromal tumor of the testis
─ ~90% are benign; ~10% are malignant (criteria for malignancy: size >5cm, infiltrative margins, vascular invasion, increased mitotic activity, necrosis, significant atypia)
Macro
─ Well-circumscribed, lobulated, solid nodule; typically yellow-tan to brown (due to lipochrome pigment)
─ Malignant tumors may be larger, show hemorrhage or necrosis
Micro
─ Diffuse sheets, nests, or trabeculae of polygonal cells with abundant eosinophilic, granular, or vacuolated (lipid-rich) cytoplasm
─ Nuclei are round, centrally located, often with a prominent nucleolus; nuclear atypia usually mild in benign cases
─ Reinke crystals: Pathognomonic; rod-shaped or rhomboid eosinophilic intracytoplasmic inclusions (present in ~30-40% of cases)
─ Lipofuscin pigment common; stroma is usually scant, well-vascularized; fibrinoid necrosis of vessels can be seen
─ Malignant features: Increased cellularity, nuclear pleomorphism, hyperchromasia, high mitotic rate (e.g., >3-5/10 HPF), atypical mitoses, necrosis, lymphovascular invasion
Ancillary studies
─ IHC (+): Inhibin-alpha (cytoplasmic/membranous), Calretinin (nuclear/cytoplasmic), SF-1 (nuclear), Melan-A (MART-1), Androgen Receptor (AR)
─ IHC (-): EMA, PLAP, OCT3/4, SALL4, Cytokeratins (usually), S100 (usually)
DDx
─ Leydig cell hyperplasia (Nodular aggregates of Leydig cells in interstitium, not a discrete mass, often bilateral)
─ Seminoma (OCT3/4+, PLAP+, clear cells, lymphocytic infiltrate)
─ Malignant melanoma (S100+, SOX10+, history of melanoma)
─ Adrenal rest tumor (Similar morphology, but often subcapsular, may be bilateral, associated with CAH)
Note
─ Most are benign; malignant behavior is rare but well-documented
Media ─ placeholder ─ Leydig cell tumour H&E ─ Leydig cell tumour H&E ─ Leydig cell tumour H&E ─ Leydig cell tumour H&E ─ Leydig cell tumour H&E H&E ─ Leydig cell tumour H&E ─ Leydig cell tumour Masson Trichrome (MST) H&E ─ Leydig cell tumour WSI ─ Leydig cell tumour - Malignant H&E ─ Leydig cell tumour infiltrating rete testis H&E

Sertoli Cell Tumor

A sex cord-stromal tumor composed of cells resembling Sertoli cells, typically forming tubules
Clinical
─ Testis; any age, but most common in middle-aged men; rare
─ Usually presents as a painless testicular mass; may be associated with estrogenic symptoms (gynecomastia) or androgenic effects (rarely)
─ Most are benign (~80-90%); malignant behavior is uncommon but associated with size >5cm, necrosis, atypia, mitoses
Macro
─ Well-circumscribed, firm, lobulated nodule; yellow-gray to white
Micro
─ Highly variable architecture; most common is tubular pattern: well-formed, hollow or solid tubules lined by columnar to cuboidal Sertoli cells
─ Other patterns: nests, cords, diffuse sheets, retiform, pseudopapillary
─ Cells: Columnar to polygonal, pale eosinophilic to clear or vacuolated cytoplasm, indistinct cell borders; nuclei oval to spindle, bland, often with inconspicuous nucleoli
─ Stroma is usually fibrous, may be hyalinized
─ Sclerosing variant: Prominent hyalinized collagenous stroma encasing tumor cells/tubules
Ancillary studies
─ IHC (+): Inhibin-alpha, Calretinin, SF-1, WT1 (nuclear), SOX9 (nuclear), Androgen Receptor (variable), Cytokeratins (AE1/AE3, CAM5.2 - often dot-like perinuclear)
─ IHC (Variable/Focal): EMA, S100
─ IHC (-): PLAP, OCT3/4, SALL4, CD99 (usually negative, unlike some ovarian Sertoli tumors)
─ Molecular: Nuclear β-catenin (CTNNB1 mutations) in a subset
DDx
─ Seminoma (OCT3/4+, PLAP+, clear cells, lymphocytic infiltrate)
─ Yolk sac tumor, tubular pattern (AFP+, Glypican-3+)
─ Leydig cell tumor (More eosinophilic cytoplasm, Reinke crystals, inhibin+, Melan-A+)
─ Testicular adenoma of rete testis (Different location, complex anastomosing channels)
Note
─ Includes "Sertoli cell tumor, NOS (not otherwise specified)"
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Large Cell Calcifying Sertoli Cell Tumor

A rare, distinctive variant of Sertoli cell tumor characterized by large cells with abundant eosinophilic cytoplasm and prominent calcifications
Clinical
─ Testis; typically occurs in younger patients (1st to 3rd decades)
─ Often bilateral and multifocal; strong association with Peutz-Jeghers syndrome and Carney complex
─ May cause isosexual precocity or gynecomastia due to hormone production (aromatase activity)
─ Generally benign, excellent prognosis; malignancy is exceptionally rare
Macro
─ Small, firm, well-circumscribed nodules; often multiple; yellowish-white; gritty due to calcification
Micro
─ Nests, cords, or tubules of large Sertoli cells with abundant, glassy, eosinophilic cytoplasm
─ Nuclei are round, often with prominent nucleoli; atypia is minimal
─ Prominent calcifications: Psammomatous, lamellar, or amorphous large calcified masses are characteristic
─ Stroma is often hyalinized; lymphocytic infiltrate may be present
Ancillary studies
─ IHC (+): Inhibin-alpha, Calretinin, SF-1, WT1, SOX9
─ IHC (-): Nuclear β-catenin (lacks CTNNB1 mutations, unlike some Sertoli cell tumor NOS)
─ Molecular: PRKAR1A mutations in Carney complex-associated cases; STK11/LKB1 mutations in Peutz-Jeghers syndrome
DDx
─ Leydig cell tumor with calcification (Leydig cells are Melan-A+, different cytology)
─ Calcifying fibrous tumor (Spindle cell lesion with collagen and psammomatous/dystrophic calcification, S100-, CD34 variable)
─ Regressed germ cell tumor (Scar, coarse calcifications, GCNIS often present)
Note
─ Bilaterality or association with Peutz-Jeghers or Carney complex should prompt genetic counseling
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Sertoli-Only Syndrome (Germ Cell Aplasia)

Histologic pattern characterized by seminiferous tubules lined only by Sertoli cells, with complete or near-complete absence of germ cells
Clinical
─ Testis; cause of male infertility (non-obstructive azoospermia)
─ May be congenital (e.g., Y chromosome microdeletions - AZFa region), acquired (e.g., post-chemo/radiation, mumps orchitis, toxins), or idiopathic
─ Patients typically have normal secondary sexual characteristics, normal or slightly elevated FSH, normal LH/testosterone, small/normal testes
Macro
─ Testes may be normal size or small and firm
Micro
─ Seminiferous tubules are typically normal to slightly reduced in diameter
─ Tubules are lined exclusively or almost exclusively by Sertoli cells; germ cells (spermatogonia, spermatocytes, spermatids, spermatozoa) are absent or severely reduced
─ Sertoli cells appear normal or may show slight immaturity; no significant atypia
─ Leydig cells in interstitium are usually normal in number and appearance, or may appear relatively prominent due to tubular atrophy
─ Thickening of tubular basement membranes and peritubular fibrosis may be present
Ancillary studies
─ IHC not usually required for diagnosis; Sertoli cells are inhibin+, SOX9+, WT1+
─ Genetic testing for Y chromosome microdeletions may be indicated
DDx
─ Maturation arrest (Spermatogenesis present but arrests at an early stage, e.g., spermatocyte level)
─ Testicular atrophy with hypospermatogenesis (Reduced numbers of all germ cell stages, but not complete absence)
─ Post-chemotherapy/radiation changes (May show Sertoli-only pattern, but also other features like vascular damage, interstitial fibrosis)
Note
─ A descriptive histologic diagnosis, not a specific disease entity itself
─ Prognosis for fertility is poor; sperm retrieval techniques (TESE) may be attempted
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Intratubular Large Cell Hyalinizing Sertoli Cell Neoplasia

A rare intratubular proliferation of large Sertoli cells with hyalinization, strongly associated with Peutz-Jeghers syndrome
Clinical
─ Testis; occurs in patients with Peutz-Jeghers syndrome (PJS)
─ Often multifocal and bilateral; may be associated with gynecomastia due to aromatase activity by neoplastic cells
─ Considered a pre-invasive or in situ lesion, or a hamartomatous/hyperplastic process rather than a true invasive tumor; does not metastasize
Macro
─ Testis may appear normal or show subtle nodularity; not typically a discrete mass
Micro
─ Seminiferous tubules are expanded and filled by a proliferation of large Sertoli cells
─ Cells: Large, polygonal, abundant pale eosinophilic or clear cytoplasm; bland nuclei, often with visible nucleoli
─ Prominent hyalinization (deposition of basement membrane-like material) within and around the affected tubules is characteristic
─ Spermatogenesis is absent in affected tubules
Ancillary studies
─ IHC (+): Inhibin-alpha, Calretinin, SF-1, WT1, SOX9
─ Molecular: Germline STK11/LKB1 mutations (characteristic of PJS)
DDx
─ Sertoli cell nodule (Pick's adenoma) in cryptorchid testis (Smaller cells, less hyalinization, associated with cryptorchidism)
─ Germ cell neoplasia in situ (GCNIS) (Atypical germ cells, OCT3/4+, PLAP+)
─ Intratubular Sertoli cell hyperplasia (Less striking hyalinization, may be seen in various settings)
Note
─ Strong association with Peutz-Jeghers syndrome is a key feature
─ Represents a neoplastic proliferation confined to tubules, or a hamartomatous lesion
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Sertoli-Leydig Cell Tumor

Extremely rare in the testis; primarily an ovarian tumor. Testicular cases are poorly characterized.
Clinical
─ Testis; very rare, any age
─ May be hormonally active (androgenic or estrogenic effects)
Macro
─ Variable; may be solid or cystic
Micro
─ Composed of variable proportions of Sertoli cells (forming tubules, cords, nests) and Leydig cells (clusters or sheets of cells with eosinophilic cytoplasm)
─ Heterologous elements (e.g., mucinous epithelium, cartilage, skeletal muscle) may be present (as in ovarian counterpart)
─ Degree of differentiation varies
Ancillary studies
─ Sertoli cells IHC (+): Inhibin, Calretinin, SF-1, SOX9
─ Leydig cells IHC (+): Inhibin, Calretinin, SF-1, Melan-A
DDx
─ Mixed germ cell tumor with sex cord-stromal elements (Teratoma with prominent Sertoli/Leydig cell differentiation)
─ Gonadoblastoma (Composed of germ cells and sex cord elements resembling immature Sertoli/granulosa cells; usually in dysgenetic gonads, OCT3/4+ germ cells)
─ Other sex cord-stromal tumors (e.g., pure Sertoli or Leydig cell tumor if one component predominates overwhelmingly)
Note
─ Due to rarity in testis, diagnostic criteria and behavior are less well-defined than for ovarian Sertoli-Leydig cell tumors. The note in the user's original document to "see ovary" is pertinent.
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Seminal Vesicle

Media normal seminal vesicle WSI WSI