Lower Urinary Tract and Male Genital System

Question 1

Ureter Congenital Anomalies

Answer 1

• ureteropelvic junction obstruction = important cause of hydronephrosis in kids.
  
  • secondary to disorganized junctional smooth muscle, excess stromal matrix, or compression by renal vessels.

Question 2

Benign Ureteral Neoplasms

Answer 2

• mesenchymal.

Question 3

Fibroepithelial Polyps

Answer 3

• small intraluminal projections in kids.

Question 4

Malignant Ureteral Neoplasms

Answer 4

• urothelial carcinomas, similar to tumors in renal pelvis and bladder.

Question 5

Ureteral Obstruction

Answer 5

• can be secondary to calculi or clots, strictures, tumors, or neurogenic bladder dysfunction.
• ureteral dilation less important than secondary renal hydronephrosis or pyelonephritis.
• sclerosing retroperitoneal fibrosis = uncommon cause of obstruction having retroperitoneal inflammation and fibrosis, encases ureters and leads to hydronephrosis.
  
  • most have no cause (Ormond disease). can be from: drugs, neoplasms, inflammation.

Question 6

Diverticula

Answer 6

• outpouchings of bladder wall that arise as congenital defects or are acquired from persistent urethral obstruction (prostatic enlargement).
• urinary stasis predisposes to infection and calculi formation, also vesicoureteric reflux.
• if have carcinoma with it, is more advanced from thinned wall.

Question 7

Exstrophy

Answer 7

• due to development failure of anterior abd wall. bladder communicates directly with overlying skin or lies as exposed sac.
• complications = chronic infection and ↑ incidence of adenocarcinoma.
• can be surgically corrected.

Question 8

Other Ureteral Anomalies

Answer 8

• vesicoureteral reflux, connections btw bladder and vagina, rectum, uterus, or umbilicus.
  
  • umbilicus is from remnant fistulous tract of urachus that connected fetal bladder and allantois.
  • urachal cyst when only central portion of tract persists.

Question 9

Acute and Chronic Cystitis

Answer 9

• UTI.
• from bacteria, TB, fungi, viruses, Chlamydia, mycoplasma.
• schistosomiasis cystitis common in middle east.
• radiation and chemo can cause inflammation and hemorrhage.
• presentation: urinary frequency, lower abd pain, and dysuria.

Question 10

Interstitial Cystitis

Answer 10

• aka chronic pelvic pain syndrome.
• chronic cystitis in women, causing pain and dysuria without infection.
• punctate hemorrhages early, then localized ulceration (Hunner ulcer) with inflammation and transmural fibrosis.
• have mast cells.

Question 11

Malacoplakia

Answer 11

• in chronic bacterial cystitis (E. coli or Proteus), in immunosuppressed pts.
• lesions are 3-4cm soft, yellow, mucosal plaques made of foamy macrophages and bacterial debris.
• macrophages have intra-lysosomal laminated calcified concretions = Michaelis-Gutmann bodies.
• have defective macrophage phagocytic or degradative function.

Question 12

Cystitis Glandularis

Answer 12

• can be in normal bladder or with chronic cystitis.
• composed of Brunn nests (nests of transitional epithelium) that grow downward into lamina propria and transform into cuboidal epithelium.
• sometimes has intestinal metaplasia.

Question 13

Cystitis Cystica

Answer 13

• in normal bladder and chronic cystitis.
• made of Brunn nests (nests of transitional epithelium that grow downward into lamina propria and transform into flattened cells lining fluid-filled cysts.

Question 14

Squamous Metaplasia of Bladder

Answer 14

• in response to injury.

Question 15

Nephrogenic Adenoma of Bladder

Answer 15

• when shed tubular cells implant and proliferate at sites of injured urothelium.
• benign although can extend into superficial detrusor muscle.

Question 16

Urothelial Tumors

Answer 16

• occur anywhere from renal pelvis to distal urethra.
• precursor lesions: non-invasive papillary tumors = most common, range of atypia that can reflect biologic behavior.
  
  • carcinoma in situ = high grade lesion of malignant cells in flat urothelium. lack cohesiveness and shed into urine.
• involvement of muscularis propria (detrusor muscle) is major determinant of outcome, 50% 5 yr mortality.
• pathogenesis: 3:1 M:F. affects urban populations more. 80% btw ages 50-80 yrs.
  
  • risk factors: cigarettes, arylamines, schistosoma haematobium infection, chronic analgesic use, long term cyclophosphamide exposure, bladder radiation.
  • 30-60% have chromosome 9 mutations, affects p16 and p15. p53.
• morphology: papillary are low grade, red excrescences 0.5-5cm in size.
  
  • CIS = mucosal reddening, granularity, or thickening without evident intraluminal mass.
    
    • multifocal. untreated - 50-75% becomes invasive.
• presentation: painless hematuria, frequency, urgency, dysuria. 60% single, 70% localized at diagnosis.
  
  • develop new tumors after excision, are new or shedding/implantation.

Question 17

Exophytic Papillomas

Answer 17

• urothelium over finger-like papillae with loose fibrovascular cores.
• low incidence of progression or recurrence.
• 98% 10 yr survival.

Question 18

Inverted Papillomas

Answer 18

• bland urothelium extending into lamina propria.
• uniformly benign.
• 98% 10 yr survival.

Question 19

Papillary Urothelial Neoplasms of Low Malignant Potential

Answer 19

• slightly larger than papillomas with thicker urothelium and enlarged nuclei, rare mitoses, infrequent invasion.

Question 20

Low-Grade Papillary Urothelial Carcinomas

Answer 20

• orderly cytology and architecture with minimal atypia.
• can invade but rarely fatal.
• 98% 10 yr survival.
• transurethral resection.

Question 21

High-Grade Papillary Urothelial Cancers

Answer 21

• have discohesive cells with anaplastic features and architectural disarray.
• high risk (80%) for rogression and metastases.
• 25% mortality rate.

Question 22

Squamous Cell Carcinomas (Bladder)

Answer 22

• associated with chronic bladder infection and inflammation.
• 3-7% of bladder cancers.
• more frequent in countries with endemic schistosomiasis.

Question 23

Mixed Urothelial Carcinomas

Answer 23

• with areas of squamous carcinoma are invasive, fungating, and/or ulcerating tumors.
• more common than purely squamous cell bladder cancers.

Question 24

Bladder Adenocarcinomas

Answer 24

• rare.
• from urachal remnants or in setting of intestinal metaplasia.

Question 25

**Mesenchymal Tumors of Bladder**

Answer 25

* rare. * **_benign_** = look like elsewhere. ex: **leiomyomas** (most common). * **_sarcomas_** = large (10-15cm), exophytic masses. * most common in kids = **embryonal rhabdomyosarcoma** * most common in adults = **leiomyosarcoma**

Question 26

**Urethritis**

Answer 26

* either gonococcal or non-gonococcal. * men usually have **prostatitis**, women usually have **cystitis**. * most common non-gonococcal = E. coli and enterics. * **Chlamydia** = 25-60% NGU in men, 20% in women. * mycoplasma is least frequent * **Reiter syndrome** = urethritis, arthritis, conjunctivitis. associated with NGU.

Question 27

**Hypospadia**

Answer 27

* **malformations of urethral canal producing aberrant openings on ventral aspect of penis**. * associated with urogenital malformations (**undescended testes**). * constriction can **predispose to UTIs**. * severe displacement **can cause sterility**.

Question 28

**Epispadia**

Answer 28

* **malformation of urethral canal that can produce aberrant openings on dorsal surface of penis**. * associated with urogenital malformations (**undescended testes**). * constriction **predisposes to UTIs**. * severe displacement **can cause sterility**.

Question 29

**Phimosis**

Answer 29

* prepuce (**foreskin**) orifice **too small to permit normal retraction.** * usually **due to inflammation**. * **predisposes to secondary infections and carcinoma from** chronic accumulation of secretions and other debris (**smegma**).

Question 30

**Penile Inflammation**

Answer 30

* involve **both glans penis and prepuce**. * **_sexually transmitted_** = syphilis, gonorrhea, chancroid, lymphopathia venereum, herpes, granuloma inguinale. * **_balanoposthitis_** = non-specific infection by other organisms (Candida, Gardnerella, anaerobic or pyogenic bacteria). * from **poor local hygiene in uncircumcised males from smegma**, can cause phimosis.

Question 31

**Condyloma Acuminatum**

Answer 31

* **benign sexually-transmited epithelial** proliferation from **HPV types 6 and 11**. * **recurs** after excision, rarely malignant. * _morphology_: **single or multiple sessile or pedunculated red papillary** excrescences 1-5mm. involves **coronal sulcus or inner prepuce**. * **branching papillae covered by hyperplastic stratified squamous epithelium, with hyperkeratosis**. **koilocytosis** common (epithelial cell vacuolation).

Question 32

**Bowen Disease**

Answer 32

* **carcinoma in situ**. involves **male or female genitalia in patients \>35yrs. ** * men present with **solitary or multiple thickened, gray-white or red shiny plaques on penile shaft**. * marked **epithelial atypia** with **lack of orderly maturation**, no invasion. * 10% transition to invasive squamous cell carcinoma. * associated with **HPV infection, type 16**.

Question 33

**Bowenoid Papulosis**

Answer 33

* **carcinoma in situ**, associated with **HPV type 16**. * **multiple, pigmented papular lesions on external genitalia in younger sexually active pts**. * indistinguishable from Bowen disease. * rarely evolves to invasive carcinoma. * frequently **spontaneously regress**.

Question 34

**Invasive Carcinoma**

Answer 34

* penile squamous cell carcinoma \<1% of cancers in american men. * higher **prevalence in uncircumcised**. * related to carcinogens in **smegma, HPV types 16 and 18.** * occurs in **men ages 40-70yrs**. * _morphology_: **epithelial thickening on glans or inner surface of prepuce**, progreses to **ulceroinfiltrative or exophytic growth eroding penile tip, shaft**, or both. * histology same as squamous cell carcinoma. * **_verrucous carcinoma_** = uncommon **well-differentiated variant, low malignant potential**. * _presentation_: **slow growth, metastases occur in inguinal and iliac lymph nodes**. * 66% 5 yr survival if only in penis. 27% with lymph node involvement.

Question 35

**Cryptorchidism**

Answer 35

* in 1% of 1yr old boys. * **failure of descent of testes**. * usually **unilateral** and isolated anomaly. * bilateral in 25%. * testes found anywhere along normal abd to scrotal sac pathway. * 5-10% from **defect in transabdominal descent** (controlled by mullerian-inhibiting substance). * most involves **abnormalities in descent through inguinal canal** (controlled by androgens), usually palpable in inguinal canal. * _morphology_: manifest as early as 2yrs old. **decreased germ cell development, thickening and hyalinization of seminiferous tubule basement membrane, and interstitial fibrosis. sparing of Leydig cells**. * **deterioration in contralateral descended testes**, suggests intrinsic defect in testicular development. * _presentation_: associated with **sterility, inguinal hernias, ↑ incidence of testicular malignancy**. * most spontaneously descend within 1st year or get orchiopexy (surgery) before 2nd bday.

Question 36

**Testicular Atrophy and ↓ Fertility**

Answer 36

* **primary** = due to developmentat abdnormality (Klinefelter syndrome). * **secondary** to cryptorchidism, vascular disease, inflammatory disorders, hypopituitarism, malnutrition, ↑ levels of FSH, exogenous androgenic or anti-androgenic hormones, readiation, chemo. * morphology same as with cryptorchidism.

Question 37

**Testicular and Epididymal Inflammation**

Answer 37

* more common in epididymis. * syphilis begins in testes, progresses to epididymis.

Question 38

**Nonspecific Epididymitis and Orchitis**

Answer 38

* **from primary urinary tract infection, reaches epididymis via vas deferens or spermatic cord lymphatics.** * **_childhood epididymitis_**: associated with congenital genitourinary abnormalities and gram (-) rod infections. * **_sexually active men \<35yrs_** = C. trachomatis and N. gonorrhoeae. * **_men \>35yrs_** = common UTI agents (E. coli and Pseudomonas). * _morphology_: **non-specific epididymal congestion, edema, neutrophilic infiltrates**. * can go to generalized suppuration. can **go to testes via efferent ductules or local lymphatics, scarring can cause infertility**. * Leydig cells not effective so **testosterone normal.**

Question 39

**Granulomatous (Autoimmune) Orchitis**

Answer 39

* presents in **middle age** as **painless to moderately tender testicular mass, sudden onset**. * **spermatic tubule granulomas**. * suspected to be **autoimmune**.

Question 40

**Gonorrhea in Testes**

Answer 40

* **retrograde extension from posterior urethra** to prostate, seminal vesicles, epididymis. * untreated ⇒ testis, **causes suppurative orchitis**.

Question 41

**Mumps in Testes**

Answer 41

* uncommon in kids but **develops in 20-30% of postpubertal men with mumps**. * acute interstitial orchitis develops **1 wk post parotid inflammation.**

Question 42

**TB in Testes**

Answer 42

* **begins in epididymis**, secondarily involves testis. * **caseating granulomas**.

Question 43

**Syphilis in Testes**

Answer 43

* congenital or acquired. * **isolated orchitis** without involvement of adnexal structures. * **nodular gummas** or **diffuse interstitial inflammation** with **edema, lymphoplasmacytic inflammation**, and **obliterative endarteritis**.

Question 44

**Testicular Torsion**

Answer 44

* **twisting of spermatic cord cuts off testicular venous drainage**. * thick-walled arteries remain patent ⇒ **intense vascular engorgement**, may cause hemorrhagic infarction. * **_neonatal_** = in utero or shortly after birth. lacks anatomic defect. * **_adult_** = present in adolescence as sudden testicular pain. associated with **bilateral anatomic defect** giving testis increased mobility (**bell-clapper abnormality**). * occurs **without cause**. is urologic emergency, need to **untwist within 6 hrs** of onset. * orchiopexy to fix it to scrotum, prevent twisting.

Question 45

**Spermatic Lipomas**

Answer 45

* involve **proximal spermatic cord**. * **fat around cord** sometimes represents **retroperitoneal** adipose tissue that has been **pulled into inguinal canal of hernia sac**.

Question 46

**Adenomatoid Tumors (Male Genitalia)**

Answer 46

* **most common benign paratesticular neoplasm**. * **small nodules of mesothelial cells near upper epididymal pole**.

Question 47

**Rhabdomyosarcomas**

Answer 47

* most common malignant tumor in kids in spermatic cord and paratesticular area.

Question 48

**Liposarcomas**

Answer 48

* most common malignant tumor in adults in spermatic cord and paratesticular tumors.

Question 49

**Testicular Germ Cell Tumors**

Answer 49

* 95% of cases. malignant. divided into seminomas and non-seminomas. * whites:blacks 6:1. * most common malignancy in men btw 15-34 yrs, 10% of cancer deaths in that age range. * _pathogenesis_: **cryptorchidism** (in 10%); **testicular dysgenesis syndrome** (TDS) which includes cryptorchidism, hypospadias, poor sperm quality. * TDS related to pesticides, estrogen in utero. * genetic = **familial clustering**, incidence of testicular carcinoma among brothers and sons of affected. * **most come from intratubular germ cell neoplasia** (iTGCN) that is **dormant until puberty**. retain expression of **OCT3/4 and NANOG** associated with **totipotentiality**. can have activating mutations of c-KIT. * _consequences_: 60% have **multiple cell types**. usually capable of rapid, wide spread dissemination, respond to therapy. * _presentation_: **painless enlargement of testis**. * **radical orchiectomy** to prevent tumor spillage. * lymphatic metastases first in **retroperitoneal paraaortic nodes**. hematogenous metastases involve **lung, then liver, brain, and bone**. * non-seminomatous more aggressive than seminomas. * **seminomas** radiosensitive. * **non-seminomas** radioresistant, present in advanced disease. chemo ⇒ 90% remission. * **choriocarcinomas** aggressive, extensive hematogenous metastases, poor prognosis. * **AFP elevated** in endodermal sinus tumors. * **high hCG** in choriocarcinomas, lower in seminomas. * **lactate dehydrogenase**, rough measure of tumor burden.

Question 50

**Seminoma**

Answer 50

* **50% of testicular germ cell tumors**. peak incidence btw **age 30-40yrs**. * _morphology_: **homogeneous, lobulated, gray-white masses**. Devoid of hemorrhage or necrosis. tunica albuginea intact. * made of **large polyhedral seminoma cells** with abundant **clear cytoplasm** (glycogen), **large nuclei, and prominent nucleoli**. * fibrous stroma makes **irregular lobules**. there is **lymphocytic infiltrate**. * positive for **c-KIT, OCT2, and placental alkaline phosphatase** (PLAP). * 15% contain **syncytiotrophoblasts, hCG present**.

Question 51

**Spermatocytic Seminoma**

Answer 51

* uncommon. In **older pts (\>65yrs)**. * little tendency to metastasize. * _morphology_: **soft, gray cut surfaces some with mucoid cysts.** * mixture of: **small cells** resembling secondary spermatocytes, **medium-sized cells with round nucleus and eosinophilic cytoplasm**, and **scattered giant cells.**

Question 52

**Embryonal Carcinoma**

Answer 52

* peak incidence btw **20-30yrs**. * **more aggressive** than seminomas. * _morphology_: **poorly demarcated, small, gray-white** masses **punctuated by hemorrhage** and/or **necrosis**. * commonly extend through tunica albuginea **into epididymis or cord**. * **primitive epithelial cell**s with indistinct cell borders, form **irregular sheets, tubules, alveoli, and papillary structures**. * frequent mitoses and giant cells. * **positive for OCT3/4, PLAP, cytokeratin, and CD30**. * negative for c-KIT.

Question 53

**Yolk Sac Tumor (Endodermal Sinus Tumor)**

Answer 53

* **most common testicular neoplasm in pts \<3yrs**. * adult cases are part of embryonal carcinoma. * _morphology_: infiltrative, **homogeneous, yellow-white mucinous tumor**. * made of **cuboidal neoplastic cells in lacelike (reticular) network**. solid areas and papillae. * **Schiller-Duval bodies** = reseble primitive glomeruli. * **eosinophilic hyaline bodies contain immunoreactive alpha-fetoprotein (AFP) and alpha-1 antitrypsin**, associated with neoplastic cells.

Question 54

**Choriocarcinoma**

Answer 54

* highly **malignant**, made of cytotrophoblastic and syncytiotrophoblastic elements. \<1% germ cell tumors. * _morphology_: **small**, can be **hemorrhagic** or **inconspicuous lesion** replaced by **fibrous scar**. * made of **polygonal**, **uniform cytotrophoblastic cells in sheets and cords**, mixed with **multinucleated syncytiotrophoblastic cells**. * **hCG** present.

Question 55

**Teratoma**

Answer 55

* shows differentiation along endodermal, mesodermal, and ectodermal lines. * in **kids**, behave as **benign** tumors, good prognosis. * **post-pubertal men: malignant** regardless of maturity or immaturity. * _morphology_: **large** (5-10cm), heterogeneous. * **hemorrhage and necrosis** suggest mixture with embryonal and choriocarcinoma. * **haphazard array of differentiated mesodermal** (muscle, cartilage, adipose), **ectodermal** (neural tissue, skin), and **endodermal** (gut, bronchial epithelium) elements. * **mature** (resemble adult tissues) or **immature** (embryonic or fetal tissues). * **malignant transformation signifies non-germ cell malignancy within teratoma**. * spreads outside testis = no response to chemo.

Question 56

**Leydig Cell Tumors**

Answer 56

* 2% testicular tumors. **btw 20-60 yrs old**. * can **produce androgens, estrogens, and/or corticosteroids**. * most **benign**, 10% invade/metastasize. * _morphology_: **circumscribed nodules** with **homogeneous golden brown cut surface**. * made of **polygonal cells with abundant granular, eosinophilic cytoplasm and indistinct cell borders.** * **lipochrome pigment, lipid droplets**, eosinophilic **Reinke crystalloids** common. * _presentation_: **testicular mass**, changes from **hormone elaboration** (gynecomastia/sexual precocity).

Question 57

**Sertoli Cell Tumors**

Answer 57

* 10% malignant. * _morphology_: **homogeneous gray-white to yellow masses**, variable size. * **tall, columnar cells in trabeculae**, form cords or tubules. * _presentation_: **testicular mass**, no changes in hormones.

Question 58

**Testicular Lymphoma**

Answer 58

* 5% testicular neoplasms. * **most common testicular tumor in pts \>60yrs**. * **diffuse, large B-cell non-Hodgkin lymphomas**. * disseminate widely. * **high incidence of CNS involvment**.

Question 59

**Hydrocele**

Answer 59

* **accumulation of serous fluid within mesothelial-lined tunical vaginalis**. * due to generalized edema.

Question 60

**Hematocele**

Answer 60

* accumulation of blood secondary to trauma, torsion, or generalized bleeding diathesis.

Question 61

**Chylocele**

Answer 61

* accumulation of lymphatic fluid secondary to lymphatic obsturction (elephantiasis)

Question 62

**Spermatocele**

Answer 62

* local cystic accumulation of semen in dilated ductuli efferentes or rete testis.

Question 63

**Varicocele**

Answer 63

* **dilated vein in spermatic cord**. * may be asymptomatic or contribute to **infertility**.

Question 64

**Malignant Mesothelioma**

Answer 64

* rare in tunica vaginalis.

Question 65

**Acute Bacterial Prostatitis**

Answer 65

* by **organisms causing UTIs** (E.coli and gram (-) rods, enterococci, and staph). * from **urinary reflux or lymphohematogenous seeding, catheterization or surgical manipulation**. * _presentation_: **fever, chills, dysuria, and boggy, markedly tender prostate**. * _dx_: via urine culture and symptoms.

Question 66

**Chronic Bacterial Prostatitis**

Answer 66

* insidious, can be **asymptomatic or associated with low back pain, suprapubic and perineal discomfort, dysuria.** * associated with **recurrent UTI, without previous prostatitis.** * same organisms as acute bacterial prostatitis. * _dx_: leukocytes and positive bacterial cultures in prostatic secretions.

Question 67

**Chronic Abacterial Prostatitis**

Answer 67

* **most common form** of prostatitis. * _presentation_: **insidious, asymptomatic or with low back pain, suprapubic and perineal discomfort, dysuria.** * _dx_: prostatic secretions contain **\>10 leukocytes per high power field**, cultures are negative.

Question 68

**Granulomatous Prostatitis**

Answer 68

* from **installation of BCG** to treat bladder cancer. * prostatic granulomas don't need tx. * **_non-specific granulomatous prostatitis_** uncommon, from **rxn to secretions from rupture prostatic ducts and acini**.

Question 69

**Benign Prostatic Hyperplasia**

Answer 69

* aka nodular hyperplasia. * common, **from periurethral epithelial and stromal hyperplasia that compresses urethra**. * **20% men by age 40; 70% men by age 60; 90% by age 70**. * **50% clinically detectable, 50% have symptoms.** * 30% white Americans \>50yrs have mod to severe symptoms. * _pathogenesis_: **mediated by dihydrotestosterone (DHT), made by stromal cells of prostate** from circulating testosterone via 5alpha-reductase, type 2. * **binds AR of stromal and epithelial cells**, activates genes ⇒ ↑ production secondary growth factors and receptors (FGF-7 in stromal cells). * **FGF-7** stimulates stromal cells proliferation and inhibits epithelial apoptosis. * **FGF-1, FGF2, and TFG-beta** ⇒ fibroblast proliferation. * _morphology_: gland enlarged by **nodules in transitional and periurethral zones**. cut surface has **well-demarcated** nodules, vary from **firm and pale gray** (mostly fibromuscular stromal) to **yellow-pink and soft** (mostly glands). * nodules made of **mixtures of proliferating glands and fibromuscular stroma**. glands lined by two layers of cells: **basal layer of low cuboidal epithelium and layer of columnar secretory cells.** * can have **squamous metaplasia and infarcts**. * _presentation_: lower urinary tract obstruction symptoms from **↑ size of prostate, extrinsic compression of urethra, and smooth muscle-mediated contraction of prostate**. * **bladder hypertrophy and distention**, urinary retention. * **urinary frequency, nocturia, difficulty starting and stopping**, chronic urinary stasis with bacterial overgrowth and **UTIs**, **urinary bladder diverticula and hydronephrosis**. * _tx_: alpha blockers, 5alpha reductase inhibitors, resection.

Question 70

**Adenocarcinoma (Prostate)**

Answer 70

* **most common form of cancer in men**. 1 in 6 lifetime risk. * **men \>50yrs**; 70% in men \>70yrs. uncommon in Asians, more common in **blacks**. * _pathogenesis_: risk factors = ↑ age, race, hormonal influences, genetics, enviromnent. * **X-linked AR gene** has CAG repeats, shorter in blacks = more sensitive, longer in Asians = less sensitive. * **↑ risk with first-degree relatives**. * **BRCA2** mutation ⇒ 20x risk. * acquired mutations: **ETS next to TMPRSS2** makes more invasive; **hypermethylated glutathione S-transferase** downregulates expression causing ↑ susceptibility to carcinogens; ↑ expression of **E-cadherin with ↓ expression EZH-2** transcription repressor. * **↑ risk with fat consumption, lycopenes, vitamin d, selenium, soy products**. * precursor lesions = **prostatic intraepithelial neoplasia** (PIN). * _morphology_: **arise in peripheral zone** usually in **posterior prostate**. * **poorly demarcated, gritty, firm, yellow**. may infiltrate seminal vesicles, urinary bladder. rarely invades rectum. * **well-demarcated adenocarcinomas with small, crowded glands lined by single layer of epithelium**, nuclei large and have nucleoli. * **perineural invasion = malignancy**. * high grade PIN = **benign but cytologically atypical cells**, see in 80% prostatic carcinomas. * **Gleason system** = 5 grades prostate cancer. * 1 = normal; 5 = no glandular differentiation. * low to mod grade = treatable; high grade = bad prognosis. * _presentation_: metastases in **obturator nodes**, spread from there. hematogenous **spread to bone** causing osteoblastic metastases. * **PSA** for diagnosis, secreted from prostatic epithelium into semen. * measure by level, velocity (rate of change). * _tx_: surgery or radiotherapy