Chapter 21: The Lower Urinary Tract and Male Genital System

 Renal pelves, ureters, bladder, and urethra (except the terminal portion) are lined by
transitional epithelium called urothelium
 Urothelium – 5-6 layers with oval nuclei, often with linear nuclear grooves, and a surface
layer consisting of large, flattened “umbrella cells” with abundant cytoplasm
 It is important to differentiate the muscularis mucosae from muscularis propria
 bladder cancers are staged on the basis of invasion of muscularis propria

URETERS
a) Congenital Anomalies of Ureters
 Double and bifid ureters – mostly unilateral
 Ureteropelvic junction (UPJ) obstruction - most common cause of hydronephrosis in
infants and children. Males in children. Women in adults and is unilateral
 Diverticula - saccular outpouchings of the ureteral wall. Hydroureter
b) Inflammation of Ureters
 Ureteritis
 lymphocytes forming germinal centers in the subepithelial region
 fine granular mucosal surface (ureteritis follicularis)
 flattened urothelium (ureteritis cystica)
c) Tumors and Tumor-like Lesions of Ureters
 Primary tumors are rare
 Fibroepithelial polyp - small mass projecting into the lumen in children
 Urothelial carcinomas – in older people. Causes obstruction
d) Obstructive Lesions of Ureters
 May cause hydroureter, hydronephrosis, and sometimes pyelonephritis
 Unilateral obstruction typically results from proximal causes
 bilateral obstruction arises from distal causes
 Sclerosing Retroperitoneal Fibrosis - fibrotic proliferative inflammation encasing the
retroperitoneal structures. Hydronephrosis.
 The disorder occurs in middle to late age and is more common in males.
 Initial treatment is corticosteroid and surgery for resistance
 IgG4 positive and eosinophils germinal centers
 Urinary Bladder
1. Cystitis is particularly common in young women
Congenital Anomalies of Urinary Bladder
a) Vesicoureteral reflux
o Most common and serious congenital anomaly.
o Major contributor to renal infection and scarring.
o congenital vesicouterine fistulae
b) Diverticula –
o Congenital diverticula may be due to a focal failure of development of the
normal musculature or to some urinary tract obstruction during fetal
development.
o Acquired diverticula are most often seen with prostatic enlargement producing
obstruction to urine outflow and marked muscle thickening of the bladder wall.
o Increased intravesical pressure
c) Exstrophy of the bladder
o Failure in the anterior wall of the abdomen and the bladder.
o Bladder either communicates directly through a large defect with the surface of
the body or lies as an opened sac.
o Exposed bladder mucosa undergo colonic glandular metaplasia and is subject to
infections
d) Urachal anomalies
o urachus is normally obliterated after birth
o Fistulous urinary tract connects the bladder with the umbilicus when totally
patent.
o Urachal cysts if only the central portion lined by metaplastic glandular
epithelium. Glandular tumors arises from this cysts
e) Inflammation of Urinary bladder
o Acute and Chronic Cystitis – Most commonly Escherichia coli, followed by
Proteus, Klebsiella, and Enterobacter.
o Tuberculous cystitis is almost always a sequel to renal tuberculosis
o Mycoplasma may also cause cystitis
o radiation cystitis
o cyclophosphamide and also Adenovirus may develop hemorrhagic cystitis
o Follicular cystitis - lymphoid follicles within the bladder mucosa and underlying
wall
o Eosinophilic cystitis - infiltration with submucosal eosinophils
o All forms of cystitis are characterized by a triad of symptoms: Polyuria,
Suprapubic pain, and Dysuria
Special Forms of Cystitis
1. Interstitial Cystitis – a.k.a Chronic Pelvic Pain Syndrome
 most frequently in women
 intermittent, often severe, suprapubic pain
 urinary frequency and urgency
 hematuria
 dysuria
 cystoscopic findings of fissures and punctate hemorrhages (glomerulations)
in the bladder mucosa after luminal distention
 empiric treatment
 associated with (Hunner ulcers); this is termed the late (classic, ulcerative)
phase
 Late phase is transmural fibrosis leading to a contracted bladder
2. Malakoplakia
 chronic bacterial infection – E. coli
 acquired defects in phagocyte function
 frequently in immunosuppressed transplant recipients
 soft, yellow, slightly raised mucosal plaques in bladder
 raised plaques filled with large, foamy macrophages mixed with occasional
multinucleate giant cells and lymphocytes
 macrophages have an abundant granular cytoplasm
 Michaelis-Gutmann bodies - laminated mineralized concretions resulting
from deposition of calcium in enlarged lysosomes
 3. Polypoid Cystitis
 irritation of the bladder mucosa
 from indwelling catheters
 submucosal edema
 may be confused with papillary urothelial carcinoma

f) Metaplastic Lesions of Bladder
1. Cystitis glandularis and cystitis cystica
 nests of urothelium (Brunn nests) grow downward into the lamina
propria
 metaplasia into cuboidal or columnar appearance (cystitis glandularis)
 or flattened urothelium (cystitis cystica)
 often coexists called cystitis cystica et glandularis
 In cystitis glandularis, goblet cells are present
2. Squamous metaplasia
 Nephrogenic adenoma - implantation of shed renal tubular cells at sites
of injured urothelium
g) Neoplasms of Bladder
1. Urothelial Tumors
 90% of all bladder tumors
 gain- of-function mutations in FGFR3 in noninvasive low-grade papillary
carcinomas
 loss-of-function mutations in the TP53 and RB tumor suppressor genes in
high-grade invasive tumors
 losses of genetic material on chromosome 9
 High Grade Lesions - confined to the epithelium, showing NO basement
membrane invasion
 Once muscularis propria invasion occurs, a 30% 5-year mortality rate
 higher in men (3:1)
 Higher in developed countries
 painless hematuria
 pyelonephritis or hydronephrosis if urethral orifice is involved
 For small, localized low-grade papillary tumors, the diagnostic
transurethral resection is the ONLY surgical procedure done
 For high grade tumors, Mycobacterium bovis is instilled in bladder called
bacillus Calmette-Guérin (BCG) and elicit a local inflammatory reaction
that destroys the tumor
 Radical cystectomy for Muscularis proria invasion, CIS, and CIS with
prostatic involvement
 Two distinct precursor lesions to invasive urothelial carcinoma
1. noninvasive papillary tumors – (most common)
2. flat noninvasive urothelial carcinoma
Morphology

 varies from purely papillary to nodular or flat

 from the lateral or posterior walls at the bladder base
 Papillary lesions are red, elevated excrescences
 majority of papillary tumors are low grade
a) Papillomas
 represent 1% or less of bladder tumors
 seen in younger patients
 arises from exophytic papillomas – small, superficial
 histologically identical to normal urothelium
 In contrast, inverted papillomas - benign lesions consisting of inter-
anastomosing cords of cytologically bland urothelium that extend down into the
lamina propria

b)
 thicker urothelium
  progression to high grade may occur
c) Low-grade papillary urothelial carcinomas
 orderly architectural and cytologic appearance
 cells are evenly spaced and cohesive
 low grade cancer

d) High-grade papillary urothelial cancers

 dyscohesive cells with large hyperchromatic nuclei
 Carcinoma in situ
1. flat urothelial carcinoma
2. pagetoid spread – full thickness atypia
3. lack of cohesiveness
4. mucosal reddening without an evident intraluminal mass
5. multifocal
 Invasive urothelial cancer
o invasion into the muscularis mucosae
Important contributors of Bladder carcinoma
a) Cigarette smoking – 3 to 7 fold risk
b) Industrial exposure to aryl amines - 2naphthylamine
c) Schistosoma haematobium – Egypt and Sudan
d) Cyclophosphamide – an immunosuppresive
e) Irradiation

2. Variants of Urothelial Carcinoma

 nested variant with deceptively bland cytology

 lymphoepithelioma-like carcinoma
 micropapillary carcinoma
3. Other Epithelial Bladder Tumors

 Squamous cell carcinomas - chronic bladder irritation and infection

 Mixed urothelial carcinomas with areas of squamous carcinoma – common
 Adenocarcinomas – rare
 Smallcell carcinomas - indistinguishable from small-cell carcinomas of the lung
4. Mesenchymal Tumors

 Benign Tumors
o rare
o most common is leiomyoma
o isolated
o intramural
o encapsulated
o oval-tospherical masses
 Sarcomas
o Inflammatory myofibroblastic tumors
o sarcomatoid growth patterns
o produce large masses
o soft, fleshy, gray-white gross appearance
o embryonal rhabdomyosarcoma – most common in children
o sarcoma botryoides - polypoid grapelike mass
o leiomyosarcoma – most common sarcoma in bladder

5. Secondary Tumors

 direct extension from primary lesions in nearby organs

h) Obstruction of Bladder

 most common cause is enlargement of the prostate gland due to nodular hyperplasia
 more common in men
 most often caused by cystocele of the bladder

Urethra

A. Inflammation of Urethra
 classically divided into gonococcal and nongonococcal causes
 Gonococcal urethritis – early venereal infection
 Nongonococcal urethritis – several other organisms
 Reactive arthritis – triad of arthritis, conjunctivitis, and urethritis

B. Tumors and Tumor-like Lesions of Urethra
 Urethral caruncle
o small, red, painful mass
o older females
o ulcerate and bleed with the slightest trauma
 Primary carcinoma of the urethra
o arising within the proximal urethra
o Adenocarcinomas are infrequent
o Women
o Cancers arising within the prostatic urethra are dealt with in the section
on the prostate
 Benign epithelial tumors
 o squamous and urothelial papillomas
o inverted urothelial papillomas
o condylomas

Penis
A. Congenital Anomalies of Penis

 Hypospadias and Epispadias

o Malformation of the urethral groove and urethral canal
o Hypospadias – ventral and more common
o Epispadias – dorsal
o associated with failure of normal descent of the testes
o and with malformations of the urinary tract
o can cause sterility
 Phimosis
o orifice of the prepuce is too small to permit its normal retraction
o from repeated infection of preputial ring and may predispose to carcinoma
o accumulation of secretions and detritus under the prepuce

B. Inflammation of Penis

 Balanoposthitis
o infection of the glans and prepuce
o Candida albicans , Gardnerella
o Smegma - desquamated epithelial cells, sweat, and debris

C. Tumors of Penis

 Benign Tumors
o Condyloma Acuminatum
 HPV type 6
 may occur on the external genitalia or perineal areas
 single or multiple sessile or pedunculated, red papillary excrescences
 acanthosis - superficial hyperkeratosis of epidermis
 koilocytosis - Cytoplasmic vacuolization of the squamous cells
 o Peyronie Disease
 fibrous bands involving the corpus cavernosum of the penis
 penile curvature and pain during intercourse

 Malignant Tumors of Penis

o Carcinoma in Situ (CIS)
 Two histologic features: Bowen disease and Bowenoid papulosis
 Bowen disease
 both men and women, older than age 35 years
 In men it tends to involve the skin of the shaft of the penis and
the scrotum
 solitary, thickened, gray-white, opaque plaque
 can also manifest on the glans and prepuce as single or multiple
shiny red, sometimes velvety plaques
 epidermis is hyperproliferative
  intact basement membrane
 Bowenoid papulosis
 sexually active adults
 younger age
 multiple reddish brown papular lesions
 HPV type 16
 NEVER develops into an invasive carcinoma

o Invasive Carcinoma
 Squamous cell carcinoma of the penis is associated with poor genital
hygiene
 Circumcision confers protection, and hence this cancer is extremely
rare among Jews and Muslims
 HPV type 16 and 18
 slowly growing
 lesions are nonpainful until they undergo secondary ulceration and
infection
 widespread dissemination is extremely uncommon
 5-year survival rate is 66%, whereas metastasis to the lymph nodes
carries a grim 27% 5-year survival
 usually begins on the glans or inner surface of the prepuce near the
coronal sulcus
 Two macroscopic patterns are seen—papillary and flat
 papillary lesions simulate condylomata acuminata and may produce
a cauliflower-like fungating mass
 Flat lesions appear as areas of epithelial thickening accompanied by
graying and fissuring of the mucosal surface
 Both are squamous cell carcinomas
 Verrucous carcinoma - exophytic well-differentiated variant of
squamous cell carcinoma that are locally invasive, but rarely
metastasize

Testis and Epididymis

 Epididymis is mostly inflammatory diseases

 testis is mostly tumors
 synorchism - fusion of the testes
 A. Congenital Anomalies – extremely rare except undescended testes

1. Cryptorchidism
 complete or partial failure of the intra-abdominal testes to descend into the
scrotal sac
 arrested germ cell development
 hyalinization and thickening of the basement membrane of the spermatic
tubules
 Leydig cells are spared
 isolated anomaly
 unilateral
 cryptorchid testis is small and firm
 may be accompanied by hypospadias
 First Transabdominal Phase – controlled by müllerianinhibiting substance
 Second Inguinoscrotal Phase - androgen-dependent and androgen-induced
release of calcitonin gene-related peptide from the genitofemoral nerve
 Orchiopexy (placement in the scrotal sac) does NOT guarantee fertility
 Cancer may also develop in the contralateral, normally descended testis

B. Regressive Changes in Testis and Epididymis

1. Atrophy and Decreased Fertility

  progressive atherosclerotic narrowing of the blood supply in old age
 end stage of an inflammatory orchitis
 cryptorchidism
 hypopituitarism
 generalized malnutrition or cachexia
 irradiation
 antiandrogens
 exhaustion atrophy (i.e. Klinefelter syndrome)

C. Inflammation of Epididymis and Testis

1. Nonspecific Epididymitis and Orchitis

 from cystitis, urethritis, prostatitis

 congenital genitourinary abnormality and infection of gram negative in children
 C. trachomatis and Neisseria gonorrhoeae for sexually active adults
 E. coli and Pseudomonas for 35 yrs older
 nonspecific acute inflammation
 suppurative necrosis of the entire epididymis
2. Granulomatous (Autoimmune) Orchitis

 middle age
 moderately tender testicular mass of sudden onset
 painless testicular mass
3. Gonorrhea

 posterior urethra to the prostate, seminal vesicles, and then to the epididymis
 suppurative orchitis
4. Mumps

 systemic viral disease

 school-aged children
 acute interstitial orchitis 1 week after parotid gland swelling
5. Tuberculosis

 caseating granulomatous inflammation

6. Syphilis
  affected in both acquired and congenital syphilis
 testis is involved first
 production of gummas
 diffuse interstitial inflammation

D. Vascular Disorders of Testis and Epididymis

1. Torsion

 Twisting of the spermatic cord typically cuts off the venous drainage of the testis
 testicular infarction
 Neonatal torsion occurs either in utero or shortly after birth.
 Adult torsion is typically seen in adolescence and presents with the sudden onset of
testicular pain
 Reversible if manually untwisted within 6 hours of the onset of torsion
 increased mobility of the testes (bellclapper abnormality) in Adult torsion
 Orchiopexy – surgical correction

E. Spermatic Cord and Paratesticular Tumors

 Lipomas - proximal spermatic cord

 Adenomatoid tumor
o most common benign paratesticular tumor
o upper pole of the epididymis
o NOT referred to as mesotheliomas
o small nodules
o If identified during surgery, patient is spared from Orchiectomy
 Rhabdomyosarcomas - most common malignant paratesticular tumors in children

F. Testicular Tumors

 Two major categories: Germ cell tumors (95%) and Sex cord-stromal tumors
 Most germ cell tumors are aggressive but curable
 Sex cord-stromal tumors, in contrast, are generally benign
1. Germ Cell Tumors
  Originates from intratubular germ cell neoplasia (ITGCN)
 From ITGCN except pediatric yolk sac tumors and teratomas, and adult spermatocytic
seminomas
 large nuclei and clear cytoplasm
 OCT3/4 and NANOG transcription factors
 reduplication of the short arm of chromosome 12 (12p) in the form of an
isochromosome i(12p)
 15- to 34-year age
 most common tumor of men
 White men (5:1)
 testicular dysgenesis syndrome (TDS) - cryptorchidism, hypospadias, and poor sperm
quality
 Klinefelter syndrome is 50x risk for mediastinal germ cell tumors but NO testicular
tumors
 relative risk of these tumors is four times higher than normal
 8 to 10 times higher in brothers
 receptor tyrosine kinase KIT and BAK (apoptotic genes)
 Seminomatous tumors - primordial germ cells or early gonocytes
 Non-seminomatous tumors - embryonic stem cells
 60% of cases the tumors contain mixtures of seminomatous and nonseminomatous

2. Seminoma

 most common type of germ cell tumor

 NEVER occur in infants
 Dysgerminoma - identical tumor that arises in the ovary
 isochromosome 12p and express OCT3/4 and NANOG
 KIT amplification and KIT overexpression
 “seminoma” refers to “classic” or “typical” seminoma
 homogeneous, graywhite, lobulated cut surface
 tunica albuginea is NOT penetrated
 sheets of uniform cells divided into poorly demarcated lobules by delicate fibrous septa
 lymphocytic infiltrate
 large and round to polyhedral and has a distinct cell membrane
 watery-appearing cytoplasm
 large, central nucleus with one or two prominent nucleoli
 stain positively for KIT, OCT4, and placental alkaline phosphatase (PLAP)
 keratin-positive
 15% of seminomas contain syncytiotrophoblasts with high HCG
3. Spermatocytic Seminoma

 rare, slow-growing germ cell tumor

 older men (>65)
 does NOT produce metastases
 prognosis is excellent
 soft, pale gray, cut surface mucoid cysts
 three cell populations; all intermixed
o medium-sized cells - most numerous, round nucleus and eosinophilic cytoplasm
o smaller cells - secondary spermatocytes
o scattered giant cells - uninucleate or multinucleate

4. Embryonal Carcinoma

 20- to 30-year age

 more aggressive than seminomas
 primary tumors are smaller than seminoma and do NOT replace the entire testis
 extension through the tunica albuginea into the epididymis
 cells grow in alveolar or tubular patterns with papillary convolutions
 sheets of cells
 Well formed glands are absent
 positive for cytokeratin and CD30, and negative for KIT
5. Yolk Sac Tumor

 endodermal sinus tumor

 most common testicular tumor in infants and children up to 3 years of age
 very good prognosis in infants and children
 in combination with embryonal carcinoma
 nonencapsulated and have a homogeneous, yellow-white, mucinous appearance
 cuboidal or flattened cells
 resembling endodermal sinuses (Schiller-Duval bodies)
 α-fetoprotein (AFP) and α1antitrypsin

6. Choriocarcinoma

 highly malignant
 NO testicular enlargement
 small palpable nodule
 Two cell type: syncytiotrophoblasts and cytotrophoblasts
 Syncytiotrophoblasts - large multinucleated cells with abundant eosinophilic vacuolated
cytoplasm containing HCG
  Cytotrophoblasts – regular, polygonal, distinct borders, clear cytoplasm; grow in cords,
single, fairly uniform nucleus
7. Teratoma

 various cellular or organoid components reminiscent of the normal derivatives of more

than one germ layer
 any age from infancy to adult
 Pure forms are fairly common in infants and children
 Large heterogeneous with solid cartilaginous, and cystic areas
 helter-skelter collection of differentiated cells
 Myxoid stroma contains neural tissue, muscle bundles, islands of cartilage, clusters of
squamous epithelium, structures reminiscent of thyroid gland, bronchial or bronchiolar
epithelium, and bits of intestinal wall or brain substance
 teratoma with malignant transformation - malignant non–germ cell tumors
 non–germ cell malignancy are chemoresistant - isochromosome 12p
 postpubertal male all teratomas are regarded as malignant
8. Mixed Tumors

 teratoma, embryonal carcinoma, and yolk sac tumor

 seminoma with embryonal carcinoma
 embryonal carcinoma with teratoma (teratocarcinoma)
 prognosis is worsened
 painless enlargement of the testis
 Biopsy is contraindicated because of risk of tumor spillage
 Instead, excision of the scrotal skin in addition to orchiectomy
 radical orchiectomy – standard management
 Lymphatic spread is common to all forms of testicular tumors
 retroperitoneal para-aortic nodes are the first to be involved
 Hematogenous spread is primarily to the lungs
 Two broad categories : seminoma and nonseminomatous germ cell tumors (NSGCTs)
 Stage I: tumor confined to the testis, epididymis, or spermatic cord
 Stage II: distant spread confined to retroperitoneal nodes below the diaphragm
 Stage III: metastases outside the retroperitoneal nodes or above the diaphragm
 Biologic markers include HCG, AFP, and lactate dehydrogenase
 Value of serum markers is fourfold
 Pure choriocarcinoma has a poor prognosis
9. Tumors of Sex Cord-Gonadal Stroma

 Leydig cell tumors and Sertoli cell tumors

 Leydig Cell Tumors
o elaborate androgens, estrogens, and even corticosteroids
o 20 and 60 years of age
o testicular swelling and gynecomastia
o sexual precocity in children
o circumscribed nodules
o golden brown, homogeneous cut surface
o lipid droplets, vacuoles, or lipofuscin pigment
o rod-shaped crystalloids of Reinke
o most are benign
 Sertoli Cell Tumors
o hormonally silent
o testicular mass
o firm, small nodules
o homogeneous gray-white to yellow cut surface
o mostly benign
  Gonadoblastoma
o mixture of germ cells and gonadal stromal elements
o becomes malignant, giving rise to seminoma
 Testicular Lymphoma
o 5% is caused by Aggressive non–Hodgkin lymphomas
o men older than age 60 years
o diffuse large B-cell lymphoma – most common
o involves CNS

G. Miscellaneous Lesions of Tunica Vaginalis

 tunica vaginalis, which is a mesothelial-lined surface exterior to the testis that may
accumulate serous fluid (hydrocele) causing enlargement of the scrotal sac
 Transillumination - clear, translucent character of the contained fluid
 Hematocele indicates the presence of blood in the tunica vaginalis
 Chylocele - accumulation of lymph in the tunica found in patients with elephantiasis
and filariasis
 Spermatocele - small cystic accumulation of semen in dilated efferent ducts or ducts of
the rete testis
 Varicocele is a dilated vein in the spermatic cord

Prostate

 prostate weighs approximately 20 gm

 retroperitoneal organ
 devoid of a distinct capsule
 Zones : peripheral, central, transitional, and periurethral zones
 most hyperplasias arise in the transitional zone
 most carcinomas originate in the peripheral zone
 Normally, basal layer of low cuboidal epithelium covered by a layer of columnar
secretory cells
 Testicular androgens control the growth and survival of prostatic cells
 Three pathology : inflammation, benign nodular enlargement, and tumors
 benign nodular enlargements are by far the most common and occur so often in
advanced age
1. Inflammation of Prostate

 Acute bacterial prostatitis

o Mostly E. coli
o Mostly from intraprostatic reflux of urine from the posterior urethra or from the
urinary bladder
o fever, chills, and dysuria
o prostate is exquisitely tender and boggy
 Chronic bacterial prostatitis
o low back pain, dysuria, and perineal and suprapubic discomfort
o history of recurrent urinary tract infections
o Diagnosis depends on leukocytosis in the expressed prostatic secretions, along
with positive bacterial cultures
 Chronic abacterial prostatitis
o most common form of prostatitis
o NO history of recurrent urinary tract infection
o more than 10 leukocytes per high-power field
o bacterial cultures are uniformly negative
 Granulomatous prostatitis
o may be specific or nonspecific
o instillation of BCG within the bladder – most common cause in U.S
o Fungal granulomatous prostatitis is typically seen only in immunocompromised
hosts
o Nonspecific granulomatous prostatitis - reaction to secretions from ruptured
prostatic ducts and acini
o bacteria are NOT seen within the tissue in nonspecific granulomatous prostatitis

2. Benign Enlargement of Prostate

 Benign Prostatic Hyperplasia or Nodular Hyperplasia

o most common benign prostatic disease in men older than age 50 years
o from nodular hyperplasia of prostatic stromal and epithelial cells
o leads to urinary obstruction
o large, fairly discrete nodules in the periurethral region of the prostate
o Nodular hyperplasia is NOT considered to be a premalignant lesion
o dihydrotestosterone (DHT) - main androgen in the prostate
o type 2 5α-reductase – DHT enzyme; located almost entirely in stromal cells
o stromal cells are responsible for androgen-dependent prostatic growth
o Type 1 5α-reductase is NOT detected in the prostate
o DHT binds to the nuclear androgen receptor (AR) present in both stromal and
epithelial prostate cells
o DHT is more potent than testosterone because it has a higher affinity for AR
o fibroblast growth factor (FGF), produced by stromal cells, is paracrine regulator
of androgen-stimulated epithelial growth during embryonic prostatic
development
o TGF-β serves as a mitogen for fibroblasts and other mesenchymal cells, but
inhibits epithelial proliferation
o early nodules are composed almost entirely of stromal cells
o epithelial nodules in late
o median lobe hypertrophy - nodular enlargement may project up into the floor
of the urethra
o glands are yellow-pink and soft
o small to large to cystically dilated glands lined by two layers of cells
o inner columnar layer and an outer layer of cuboidal or flattened epithelium
o diagnosis of BPH CANNOT usually be made on needle biopsy
o urinary obstruction
o smooth muscle mediated prostatic contraction
o inability to empty the bladder completely
o increased urinary frequency
o nocturia
o difficulty in starting and stopping the stream of urine
o overflow dribbling
o dysuria (painful micturition)
o increased risk of developing bacterial infections of the bladder and kidney
o Medical therapy are α-blockers (α1-adrenergic receptors) and 5-α-reductase
inhibitors
o Transurethral resection of the prostate (TURP) – gold standard
3. Tumors of Prostate

 Adenocarcinoma
o most common form of cancer in men
o Prostate cancer is tied with colorectal cancer in terms of cancer mortality
o One in Six lifetime probability of being diagnosed with prostate cancer
o Common in older than age 50 years
o uncommon in Asians but common in Black
o Androgens play an important role in prostate cancer
o Kennedy disease - muscle cramping and weakness; CAG repeats
o most tumors eventually become resistant to androgen blockade
o Bypass of need for AR will increase PI3K/AKT signaling pathway; in resistance
o loss of the PTEN tumor suppressor gene; in resistance
o first-degree relative with prostate cancer have twice the risk
o two first-degree relatives have five times the risk
o germline mutations of the tumor suppressor BRCA2 have a 20-fold increased
risk
o germline mutation in HOXB13
o chromosomal rearrangements that juxtapose the coding sequence of an ETS
family transcription factor gene (most commonly ERG or ETV1) next to the
androgen regulated TMPRSS2 promoter which is common in Caucasian cohorts
o Prostate cancer - amplification of the 8q24 locus containing the MYC oncogene
and deletions involving the PTEN tumor suppressor
o In late stage - loss of TP53 and RB
o hypermethylation of the glutathione S-transferase (GSTP1) gene - most common
epigenetic alteration
o GSTP1 gene is located on chromosome 11q13 and is an important part of the
pathway that prevents damage from a wide range of carcinogens
o Prostate carcinoma is the product of acquired genomic structural changes,
somatic mutations and epigenetic changes
o prostatic intraepithelial neoplasia (PIN) - putative precursor lesion
o PIN and cancer typically predominate in the peripheral zone
o Unlike in cancer of the cervix, the term “carcinoma in situ” is NOT used for PIN
o Prostate carcinoma arises in the peripheral zone in a posterior location
o neoplastic tissue is gritty and firm
o extremely difficult to visualize
o more readily apparent on palpation
o Hematogenous spread – osteoblastic and usually in axial skeleton (lumbar spine)
o most lesions are adenocarcinomas
o well-defined, readily demonstrable gland patterns
o benign glands and are lined by a single uniform layer of cuboidal or low
columnar epithelium
o prostate cancer glands are more crowded, and characteristically lack branching
and papillary infolding
o outer basal cell layer typical of benign glands is absent in prostate cancer
o Diagnosis - constellation of architectural, cytologic, and ancillary findings
o α-methylacyl-coenzyme A-racemase (AMACR), which is increased in prostate
cancer
o AMACR is still prone to false-positive and false-negative results and must be
used in conjunction with the routine hematoxylin and eosin–stained sections
o PIN - benign large, branching prostatic acini lined by cytologically atypical cells
with prominent nucleoli
 o Unlike malignant glands, PIN glands are surrounded by a patchy layer of basal
cells and an intact basement membrane
o grade and stage are the best prognostic predictors
o Prostate cancer is graded using the Gleason system

Five grades on the basis of glandular patterns of differentiation

 Grade 1 - well differentiated tumors, neoplastic glands are uniform and round in
appearance and are packed into well-circumscribed nodules
 Grade 5 - NO glandular differentiation, tumor cells infiltrating the stroma in the form of
cords, sheets, and nests
 Other grades fall in between these extremes
 Primary grade is assigned to the dominant pattern
 Secondary grade to the second most frequent pattern
 Two numeric grades are then added to obtain a combined Gleason grade
 Tumors with only one pattern are treated as if their primary
 most well-differentiated tumors have a Gleason score of 2
 least-differentiated tumors merit a score of 10 (5 + 5)
 2 to 6 is excellent prognosis
 3 + 4 = 7 is moderately differentiated tumors
 4 + 3 = 7 is moderately to poorly differentiated tumors
 8 to 10 is poorly to undifferentiated tumors with aggressive biologies
 In surgery, 2 to 4 are typically small tumors in TURP in BPH
 6 to 7 – detectable by needle biopsy ; potentially treatable

 Staging of prostatic cancer is important in the selection of therapy

 T1 - incidentally found cancer, either on TURP done for BPH symptoms OR elevated
PSA

 T2 - organ-confined cancer

 T3a and T3b - extra-prostatic extension, with or without seminal vesicle invasion

 T4 - direct invasion of contiguous organs

 Stage T1a cancers found on TURP do NOT progress when followed for 10 or more years
 Localized prostate cancer is asymptomatic
 Most prostatic cancers arise peripherally away from the urethra, and therefore urinary
symptoms occur late
 Osteoblastic metastases - virtually diagnostic of this form of cancer in men
 Digital rectal examination - low sensitivity and specificity
 Transrectal needle biopsy - required to confirm the diagnosis
 Serum PSA - to assist with the diagnosis and management
 PSA - from prostatic epithelium secreted in semen
 PSA – is an androgen-regulated serine protease to cleave and liquefy the seminal
coagulum formed after ejaculation
 PSA is organ specific but NOT cancer specific
 Serum PSA level of 4 ng/mL – cutoff for normal
 Changes or refinement to PSA readings includes:
o Serum PSA value : PSA density ratio
o Rate of change in PSA value with time (PSA velocity)
o Age-specific reference ranges
o Free to Bound Serum PSA ratio
 PSA density - divide the Total serum PSA by the estimated gland volume (from
ultrasound)
 older men would have higher serum PSA levels than younger men
 Upper agespecific PSA reference ranges are
o 40 to 49 years - 2.5 ng/mL
o 50 to 59 years - 3.5 ng/mL
o 60 to 69 years - 4.5 ng/mL
o 70 to 79 years - 6.5 ng/mL
 In 40 yrs old - PSA value of 3.5 is worrisome
 Normal rate of change in PSA is 0.75 ng/mL/year (measured 3x a year in 1.5 to 2 years)
 Immunoreactive PSA (detected by antibody test) exists in two forms
o major fraction bound to α1-antichymotrypsin
o minor free fraction
 Percentage of free PSA is lower in prostater cancer than BPH
 Rising PSA level after radical prostatectomy or radiotherapy for localized disease is
indicative of recurrent or disseminated disease
 PCA3 - noncoding RNA which is overexpressed in 95% of prostate cancers.
 Urine PCA3 – additional biomarker for diagnosis of prostate cancer
  Urinary PCA3 with screening of urine for TMPRSS2ERG fusion DNA has higher sensitivity
and specificity than PSA screening alone.

 Prostate CA is treated by surgery, radiation therapy, and hormonal manipulations

 Radical prostatectomy - most common treatment for localized prostate cancer

 Alternatives are brachytherapy - placing radioactive seeds throughout the prostate

 External beam radiation therapy – for more advanced cancer

 Advanced metastatic carcinoma is treated by androgen deprivation therapy

 Androgen deprivation by orchiectomy, or by synthetic analogs of luteinizing hormone-

releasing hormone (LHRH) which suppress normal LHRH

 pharmacologic blockade of the androgen receptor

 Resistance to testosterone withdrawal - disease progression and death

Miscellaneous Tumors and Tumor-like Conditions in Prostate

 Prostate adenocarcinomas may also arise from prostatic ducts

 Ductal adenocarcinomas in peripheral ducts is similar to prostate CA
 But those arising in the larger periurethral ducts is similar to urothelial cancer with
hematuria and urinary obstructive symptoms
 Ductal adenocarcinomas has poor prognosis
 Prostate CA either adenosquamous or pure squamous cancer
 Colloid carcinoma of the prostate - abundant mucinous secretions
 Small-cell cancer (neuroendocrine carcinoma) – most aggressive
 Urothelial cancer - most common tumor to secondarily involve the prostate
o Large invasive urothelial CA - directly invade from the bladder into prostate
o Carcinoma in situ of the bladder - extend into the prostatic urethra and down
into the prostatic ducts and acini
 Lymphomas may appear to first arise in the prostate, most patients shortly thereafter
demonstrate systemic disease