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Penis - congenital anomalies, inflammations & tumors CONGENITAL ANOMALIES • Hypospadias and Epispadias - Abnormal openings either on the ventral surface of the penis (hypospadias) or on the dorsal surface (epispadias). - Malformation of the urethral groove and canal -Associated with failure of normal descent of the testes and malformations of the urinary tract - Clinical significance: opening may often be constricted resulting in urinary tract obstruction and increased risk of ascending UTIs; : opening is near the base of the penis, normal ejaculation and insemination are blocked causing sterility in men • Phimosis - Conditiion in which the orifice of the prepuce is too small too permit its normal retraction - Result from anomalous development; frequent repeated attacks of infection that cause scarring of the preputial ring - Clinical significance: favors development of secondary infections and carcinoma - paraphimosis: marked constriction and swelling will block the prepuce; due to forced retraction over the glans penis INFLAMMATIONS - Usually involve the glans and prepuce - Specific infections : syphilis, gonorrhea, chancroid, granuloma inguinale, lymphopathia venerea, genital herpes - Non specific infection: balanoposthitis - balanoposthitis is infection of the glans and prepuce; caused by C. albicans, anaerobic bacteria, Gardnerella, and pyogenic bacteria -Due to poor local hygiene in uncircumcised males, with accumulation of smegma which acts as local irritant TUMORS • Benign Tumors Condyloma Acuminatum – caused by human papillomavirus (HPV) type 6 and 11 - Related to the common wart ( verruca vulgaris); occur in the genital areas in either sex - morphology: on the penis, occur most often about the coronal sulcus & inner surface of the prepuce : consist of single or multiple sessile or pedunculated, red papillary excrescences from 1 mm to several mm in diameter -micro: branching, villous, papillary connective tissue stroma covered by epithelium :epithelium shows vacuolization ( koilocytosis which is characteristic of HPV infection) : tend to recur but do not develop into invasive carcinoma • Malignant Tumors Carcinoma in Situ – or high grade squamous intraepithelial carcinoma - malignant cells are confined to the epithelium, with no evidence of local invasion or distant mets - precancerous condition a. Bowen disease – both men & women, over 35 years; in men, it involves the skin of the shaft of the penis and scrotum - grossly: solitary, thickened, gray white, opaque plaque with shallow ulceration & crusting - in the glans & prepuce, appears as single or multiple shiny red, velvety, plaques referred to as Erythroplasia of Queyrat - histo: epidermis shows proliferation with numerous mitoses, some atypical; cells are markedly dysplastic with large hyperchromatic nuclei & lack of orderly maturation - occurrence of visceral cancer in 1/3 of patients may develop into infiltrating squamous cell CA in approx 10% of patients b. Bowenoid papulosis – occurs in sexually active adults - gross: multiple, reddish brown papular lesions - never develops into invasive carcinoma & spontaneously regresses in many cases Invasive Carcinoma – Squamous Cell Carcinoma - uncommon malignancy, < 1% of cancers in males; associated with circumcision; HPV type 16 & 18; affects males, 40 to 70 years - Gross: begins on the glans or inner surface of prepuce near the coronal sulcus : two patterns – papillary & flat : papillary – simulate condyloma acuminata; cauliflower-like fungating mass : flat – appear as areas of epithelial thickening with graying & fissuring of mucosal surface; ulcerated papule usually develops - histo: both papillary & flat lesions are squamous cell CA with varying degrees of differentiation - Verrucous carcinoma: uncommon, well-differentiated variant of squamous cell carcinoma with low malignant potential; locally invasive but rarely metastasize - other subtypes: basaloid, warty and papillary - clinical course: slow growing, locally invasve; not painful unless there is ulceration & infection; frequently bleeds; inguinal & iliac LN mets in early stage; widespread dissemination uncommon - prognosis: 66% 5- year survival rate without involvement of inguinal LN : 27% 5-year survival with LN mets Testis and Epididymis CONGENITAL ANOMALIES Cryptorchidism – undescended testes ; 1% of 1 yearold boys - complete or incomplete failure of the intra-abdominal testes to descend into the scrotal sac Two phases of testicular descent: a. Transabdominal phase – testis lie within the lower abdomen or brim of the pelvis; controlled by mullerian inhibiting substance - 5% to 10 % of cases b. Inguinoscrotal phase – testes descend through the inguinal canal into the scrotal sac; androgen dependent; mediated by androgen-induced release of calcitonin gene-related peptide from the genitofemoral nerve - morphology : unilateral in most cases; bilateral in 25% of patients - histo: arrest in development of germ cells with marked hyalinization & thickening of basement membrane of spermatic tubules - concomitant increase in interstitial stroma and prominent Leydig cells - Cryptorchid testis is small, firm due to the fibrotic changes -Contralateral (descended testis) has also been noted to be deficient in germ cells in patients with unilateral cryptorchidism - Bilateral cryptorchidism will lead to sterility; infertility also noted in cases of uncorrected unilateral cryptorchidism - Undescended testis is at greater risk of developing carcinoma than is the descended testis REGRESSIVE CHANGES Atrophy – causes: a. Progressive atherosclerotic narrowing of blood supply in old age b. End stage of an inflammatory orchitis c. cryptorchidism d. hypopituitarism e. Generalized malnutrition or cachexia f. irradiation g. Prolonged administration of female sex hormones in treatment of patients with carcinoma of prostate h. Exhaustion atrophy Findings Associated with Decreased Fertility a. hypospermatogenesis b. maturation arrest c. vas deferens obstruction INFLAMMATIONS - More common in the epididymis than in the testis - gonorrhea & tuberculosis arise in the epididymis; syphilis affects the testis first Non-Specific Epididymitis and Orchitis - commonly related to infections in the urinary tract - In childhood, epididymitis is associated with congenital genitourinary abnormality & infection with Gmnegative rods - Chlamydia trachomatis & Neisseria gonorrhoeae: sexually active males < 35 years - E. coli & Pseudomonas: males >35 years - morphology: congestion, edema & infiltration by neutrophils, macrophages & lymphocytes : limited to the interstitial connective tissue and extends to the tubules and may progress to frank abscess or suppurative necrosis of the entire epididymis - Extend to the testis; fibrous scarring of both epididymis & testis will lead to sterility; interstitial cells of Leydig not completely destroyed Granulomatous (Autoimmune) Orchitis - rare cause of unilateral testicular enlargement in middle aged men - sudden onset of moderately tender testicular mass associated with fever - histo: granulomas confined within spermatic tubules Specific Inflammations Gonorrhea - Infection is from posterior urethra → prostate → seminal vesicles → epididymis - Can spread to the testis & produce suppurative orchitis Mumps - Systemic viral disease; commonly affects schoolage children; testicular involvement is uncommon - Orchitis may develop in 20% to 30% of postpubertal males; develops about 1 week after onset of swelling of the parotid glands Tuberculosis - Begins in the epididymis & may spread to the testis - Usually represents a secondary spread from other involvements of the genital tract ( tuberculous prostatitis, seminal vesiculitis) - Appears as caseating granulomatous inflammation Syphilis - Both are affected in acquired and congenital syphilis - Production of gummas or a diffuse interstitial inflammation (edema, lymphocytic and plasma cell infiltration) with characteristic hallmark of all syphilitic infecions ( obliterative endarteritis with perivascular cuffing of lymphocytes & plasma cells) VASCULAR DISTURBANCES Torsion - Twisting of the spermatic cord; cut off venous drainage and arterial supply to the testis - Two types: neonatal torsion occurs in utero or after birth; lacks associated anatomic defect : adult torsion is seen in adolescence; sudden onset of testicular pain; results from bilateral anatomic defect ( bell clapper abnormality) - morphology: range from intense congestion to widespread extravasation of blood into the interstitial tissue of the testis & epididymis - Late stages, testis is markedly enlarged & converted into a sac of soft, necrotic, hemorrhagic tissue Spermatic Cord and Paratesticular Tumors - Lipomas are common in the proximal spermatic cord - Adenomatoid tumor, most common benign paratesticular tumor : usually small nodules near the upper pole of the epididymis; well-circumscribed, minimally invasive into the surrounding tissue - Most common malignant paratesticular tumors are rhabdomyosarcoma (children) and liposarcoma (adults) TESTICULAR TUMORS -Two major categories: germ cell tumors : nongerminal tumors Pathologic Classification of Common Testicular Tumors Germ Cell Tumors Seminoma Spermatocytic Seminoma Embryonal Carcinoma Yolk Sac (Endodermal Sinus) Tumor Choriocarcinoma Teratoma Sex cord-Stromal Tumors Leydig Cell Tumor Sertoli Cell Tumor Germ Cell Tumors Seminoma - Most common type of germinal tumor (50%) - Uniform population of cells - Almost never occur in infants; peak in the thirties - In the ovaries, it is called dysgerminoma - morphology: • classic or typical seminoma – bulky masses; 10x the the normal size • gross: homogeneous, gray-white, lobulated cut surface, devoid of hemorrhage or necrosis : tunica albuginea is not penetrated but extension to the epididymis, spermatic cord, or scrotal sac may occur • micro: sheets of uniform cells divided into poorly demarcated lobules by delicate septa of fibrous tissue : classic seminoma cell is large, round to polyhedral with distinct cell membrane; clear or wateryappearing cytoplasm & large central nucleus with one or two prominent nucleoli : cytoplasm contains glycogen : cells do not contain alpha- fetoprotein (AFP) or human chorionic gonadotropin (HCG) : stain positively for placental alkaline phosphatase : 15% of seminomas contain syncytiotrophoblasts; serum HCG levels are elevated ; septa is infiltrated with T lymphocytes : “anaplastic seminoma” shows greater cellular & nuclear irregularity with more frequent tumor giant cells & many mitoses Spermatocytic Seminoma - do not arise from an intratubular germ cell neoplasia - uncommon tumor (1% to 2% of all testicular germ cell neoplasms) - affects males over 65 years; slow- growing tumor; rarely metastasize; excellent prognosis • gross: larger than classic seminoma; pale gray, soft, cut surface sometimes with mucoid cysts • micro: three cell populations, all intermixed a. medium-sized cells (15-18 µm) – most numerous; round nucleus & eosinophilic cytoplasm b. Smaller cells (6-8 µm) – narrow rim of eosinophilic cytoplasm resembling secondary spermatocytes c. Scattered giant cells (50-100 µm) – either uninucleate or multinucleate Embryonal Carcinoma - 20 to 30 year age group - more aggressive than seminomas • gross: smaller than seminoma; does not involve the entire testis : cut sections, mass is variegated, poorly demarcated with foci of hemorrhage & necrosis : extension to the epididymis or cord is rare • micro: alveolar or tubular patterns, sometimes with papillary convolutions : undifferentiated lesions present as sheets of cells; epithelial, large & anaplastic with hyperchromatic nuclei & prominent nucleoli : mitotic figures & tumor giant cells - Syncytial cells containing HCG & cells containing AFP are detected by immunoperoxidase techniques Yolk Sac Tumor - Infantile embryonal carcinoma or endodermal sinus tumor - most common testicular tumor in infants & children up to 3 years; very good prognosis - adults, pure form is rare; frequently, yolk sac occur in combination with embryonal carcinoma • gross: nonencapsulated with homogeneous, yellow white, mucinous appearance • micro: lace-like (reticular) network of cuboidal or elongated cells; papillary structures or solid cord of cells : structures resembling endodermal sinuses (Schiller-Duval bodies) seen in 50% of cases : tumor cells contain AFP and alpha1-antitrypsin Choriocarcinoma - Highly malignant testicular tumor composed of both syncytiotrophoblastic and cytotrophoblastic cells - Also arise in the placental tissue, ovary or sequestered rests of totipotential cells (mediastinum or abdomen) • gross: no testicular enlargement; small palpable nodule (< 5 cm in diameter); hemorrhage & necrosis common • micro: contain two types of cells : syncytiotrophoblastic cell is large with many irregular or lobular hyperchromatic nuclei & abundant eosinophilic vacuolated cytoplasm; contain HCG : cytotrophoblastic cell – polygonal, distinct cell border & clear cytoplasm; cords & masses with single, uniform nucleus Teratoma - Group of complex tumors with various cellular or organoid components derived from more than one germ layer - Any age, infancy to puberty - Pure teratoma common in infants & children - morphology: large tumors (5 to 10 cm in diameter) : heterogeneous, with solid, sometimes cartilaginous & cystic areas : hemorrhage & necrosis denotes admix ture with embryonal CA, chorioCA or both : helter-skelter collection of undifferentiated cells or organoid structures (neural tissue muscle bundles, islands of cartilage, squamous epithelium, thyroid gland, bronchial or bronchiolar epith, intestinal wall or brain substance all embedded - non-germ cell tumors arising in a teratoma ; tera toma with malignant transformation; derivatives of one or more germ cell layers (focus of SQ cell CA, mucin-secreting adenoCA or sarcoma) - Good prognosis in children - In postpubertal male, all teratomas are malignant & capable of metastatic behavior, regardless whether the elements are mature or immature Mixed Tumors - 60% of cases; common mixtures include teratoma, embryonal CA & yolk sac tumor; seminoma with embryonal CA;& embryonal CA with teratoma (teratocarcinoma) Two broad categories of testicular tumors: - Seminoma - Nonseminomatous germ cell tumor (NSGCT) Clinical Manifestations of Testicular Tumors - Painless enlargement of the testis - Characteristic mode of spread: lymphatic spread – common to all forms of testicular tumors; first to be involved are the retroperitoneal para-aortic nodes - mediastinal and supraclavicular nodes hematogenous spread – lungs; liver, brain & bones - Histology of metastases maybe different from that of the testicular lesion: teratoma may show foci of choriocarcinoma in the lymph nodes • Clinical Differences Between Seminoma & NSGCT - seminoma: remain localized to the testis for a long time; approx 70 % present in clinical stage I - NSGCT: approx 60% present with advanced stage (stages II & III) - seminoma: metastases involved lymph nodes -NSGCT: mets occur earlier & use the hematogenous route more frequently : pure choriocarcinoma most aggressive of the NSGCT; spreads predominantly & rapidly by the bloodstream; involves the lungs & liver - seminoma: extremely radiosensitive - NSGCT: relatively radioresistant Three Clinical Stages of Testicular Tumors 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 - Germ cell tumors of the testis secrete polypeptide hormones & certain enzymes detected in blood by sensitive assays - Biologic markers: α-fetoprotein (AFP); human chorionic gonadotrophin ( HCG); placental alkaline phosphatase, placental lactogen & lactate dehydrogenase (LDH) - Molecular markers in diagnosis of GCT: transcription factor encoded by OCT3/4 gene, X chromosome; detected by immunoperoxidase & PCR techniques • LDH: also produced in skeletal & cardiac muscles; elevation not specific for GCT; degree of elevation correlates with the mass of tumor cells • AFP: major serum protein of the early fetus; synthesized by the fetal gut, liver cells, & yolk sac; one year after birth, serum levels of AFP fall to < 16 ng/ml • HCG: glycoprotein consisting of two dissimilar polypeptide units, α and β; synthesized & secreted by placental syncytiotrophoblast • ↑ serum AFP is produced by yolk sac tumors; ↑ HCG is produced by choriocarcinoma Value of Serum Markers in Testicular Tumors is Fourfold: In the evaluation of testicular masses In the staging of testicular germ cell tumors; persistent elevation of HCG or AFP after orchiectomy indicates stage II disease even if LN appear normal by CT scan In assessing tumor burden; levels of LDH are related to tumor mass In monitoring the response to therapy • Prognosis: -seminoma: best prognosis; > 95% of patients with stage I & II disease can be cured -NSGCT: approx 90% of patients can achieve complete remission with aggressive chemotherapy : pure choriocarcinoma has the poorest prognosis Tumors of Sex Cord-Gonadal Stroma Leydig (Interstitial) Cell Tumors - Derived from the stroma; may elaborate androgens or combinations of androgens & estrogens, and corticosteroids - Affects any age, more common in 20-60 years of age -Most common presenting feature is testicular swelling; in some patients, gynecomastia maybe the 1st symptom -In children, hormonal effects (sexual precocity) are the dominating features - morphology: circumscribed nodules < 5 cm in diameter : cut section shows distinct golden, golden brown surface : micro- Leydig cells are large, round or polygonal with abundant granular eosino- philic cytoplasm with a round central nucleus; cytoplasm contains lipid granules, vacuoles or lipofuscin pigment : characteristic rod-shaped crystalloids of Reinke occur in 25% of the tumors : 10% of the tumor in adults are invasive; most are benign Sertoli Cell Tumors (Androblastoma) -Composed entirely of Sertoli cells or may have a component of granulosa cells -Induce endocrinologic changes; either estrogens or androgens may be elaborated infrequently to cause precocious masculinization or feminization; gynecomastia appears occasionally - morphology: firm, small nodules with homogeneous gray-white to yellow cut surface : histo – tumor cells are arranged in trabeculae & form cordlike structures resembling immature seminiferous tubules - Most are benign; 10% are anaplastic & malignant Gonadoblastoma -Rare neoplasms containing mixture of germ cells & gonadal stromal elements, arising in dysgenetic gonads -Germ cell component becomes malignant giving rise to invasive seminoma Testicular Lymphoma -Not a primary tumor of the testis; affected patients present with only a testicular mass -Account for 5% of testicular neoplasm; most common form of testicular neoplasm in men over 60 years - Disseminated disease already present at the time of detection of the testicular mass - Histologic type is the diffuse large cell lymphoma; prognosis is extremely poor MISCELLANEOUS LESIONS OF THE TUNICA VAGINALIS - Serosa-lined sac proximal to the testis & epididymis -hydrocele: accumulation of clear serous fluid leading to enlargement of scrotal sac -Hematocele: presence of blood in the tunica vaginalis; uncommon condition caused by direct trauma to the testis or torsion of the testis or in hemorrhagic diseases -chylocele: accumulation of lymph in the tunica vaginalis; present in patients with elephantiasis because of the widespread, severe lymphatic obstruction -spermatocele: small cystic accumulation of semen in dilated efferent ducts or ducts of the rete testis - varicocele: collection of dilated veins in the spermatic cord; asymptomatic; may cause infertility Prostate -Weighs approx 20 grams; retroperitoneal organ encircling the neck of the bladder & urethra without a distinct capsule - Four distinct zones or regions: peripheral, central, & transitional zones & the region of the anterior fibromuscular stroma -Types of proliferative lesions are different in each region most hyperplasias arise in the transitional zone; most carcinomas originate in the peripheral zone -histologically: compound tubuloalveolar organ with small to large glandular spaces lined by epithelium : two layers of cells- basal layer of low cuboidal epithelium covered by a layer of columnar secretory cells : presence of small papillary inbuddings of the epithelium : glands all have distinct basement membrane, separated by abundant fibromuscular stroma -Three pathologic processes affect the prostate gland: inflammation, benign nodular enlargement, & tumors INFLAMMATIONS • Acute bacterial prostatitis – results from bacteria that cause urinary tract infection; E. coli, other Gramnegative rods, enterococci & staphylococci - intraprostatic reflux of urine from the posterior urethra or from the urinary bladder - lymphohematogenous routes from distant foci of infection - follows surgical manipulation on the urethra or prostate gland itself (catheterization, cystoscopy, urethral dilation or prostatic resection - fever, chills & dysuria; prostate is tender and boggy on rectal examination • Chronic bacterial prostatitis – low back pain, dysuria, & perineal & suprapubic discomfort - recurrent urinary tract infection ( cystitis, urethritis) caused by the same organism • Chronic abacterial prostatitis – most common form of prostatitis - no history of recurrent urinary tract infection - expressed prostatic secretions contain > 10 leukocytes/hpf; negative bacterial cultures - morphology: • acute prostatitis- minute, disseminated abscesses; large, coalescent focal areas of necrosis; diffuse edema, congestion & boggy suppuration • chronic prostatitis (bacterial & abacterial) – aggregation of numerous lymphocytes, plasma cells & macrophages BENIGN ENLARGEMENT • Nodular Hyperplasia ( Benign Prostatic Hyperplasia) - Common in men over age 50 - Characterized by hyperplasia of prostatic stromal and epithelial cells - Formation of large, discrete nodules in the periurethral region of the prostate - Nodules compress & narrow the urethral canal to cause partial or complete obstruction of the urethra Incidence: seen in approx 20% of men 40 years of age; 70% by age 60; 90% by age 70 Etiology & Pathogenesis - Prostatic enlargement is related to the action of androgens; prepubertal castration prevents the development of nodular hyperplasia - Dihydrotestosterone (DHT), a metabolite of testosterone, is the ultimate mediator of prostatic growth -Estrogens also promotes prostatic growth by rendering cells more susceptible to the action of DHT - Clinical symptoms of lower urinary tract obstruction in prostatic hyperplasia are also due to smooth muscle-mediated contraction of the prostate -Tension of prostate smooth muscle is mediated by the α1- adrenoreceptor localized to the stroma -Therapy with 5α-reductase inhibitor markedly reduces DHT content of the prostate, decrease in prostatic volume & urinary obstruction Morphology -Prostate weighs 60-100 gm; nodular hyperplasia is common in the inner aspect of the prostate gland (transition zone) -gross: nodules vary in color & consistency; nodules with glandular proliferation, yellow-pink, soft consistency & milky white fluid oozing out -In fibromuscular growth, nodule is pale gray, tough, does not exude fluid & less clearly demarcated from the surrounding capsule -micro: hallmark of BPH is nodularity due to glandular proliferation or dilation & to fibromuscular prolieration of the stroma : aggregations of small to large to cystically dilated glands lined by two layers, inner columnar & outer cuboidal or flattened epithelium on an intact BM : two other histologic changes associated with BPH are (1) foci of squamous metaplasia & (2) small areas of infarction Clinical Course – symptoms are related to: (1) compression of the urethra with difficulty of urination & (2) retention of urine in the urinary bladder (distention & hypertrophy of bladder, infection of the urine, cystitis & renal infections) - frequency, nocturia, difficulty in starting & stopping the stream of urine, overflow dribbling & dysuria (painful micturition) - sudden, acute urinary retention; inability to empty the bladder completely→residual urine → infection - secondary changes in the bladder: hypertrophy, trabeculum & diverticulum formation Nodular hyperplasia is not considered to be a premalignant lesion -treatment: mild cases - ↓ fluid intake, moderate intake of alcohol & caffeine-containing products; α-blockers; agent that inhibits DHT : moderate to severe cases: TURP; high-intensity focused ultrasound, laser therapy, hyperthermia, transurethral electrovaporization, intraurethral stents, : moderate to severe cases: TURP; high-intensity focused ultrasound, laser therapy, hyperthermia transurethral electrovaporization, intraurethral stents, & transurethral needle ablation using radiofrequency TUMORS Adenocarcinoma – most common form of cancer in men & the second leading cause of cancer death • Incidence - Disease of men over age 50; increases from 20% of men in fifties to 70 % in men between 70 & 80 years - Common among black Americans; uncommon in Asians • Etiology - several risk factors: age, race, family history, hormone levels & environmental influences - Linked to germ line inheritance of prostate cancer susceptibility genes; 1/3 of familial cases, a susceptibility gene has been mapped to chromosome 1q2425; other loci are C 8p, 10q, 13q & 16q - p53 mutations are seen in metastatic prostate CA; other tumor-suppressor genes in prostate cancer are PTEN & KAI1 - Frequent loss of E-cadherin & CD44 - HER-2/neu levels are low in prostatic CA; transcription factor EZH2 is present in locally aggressive & metastatic prostate cancer - Most common genetic alterations in prostate cancer is hypermethylation of glutathione S-transferase (GSTP1) gene promoter located on C 11q13 • Morphology -70& of cases, arises in the peripheral zone of the gland, in the posterior location, palpable on rectal exam - gross: on cross-section, the neoplastic tissue is gritty & firm - Spread occurs by direct local invasion ( seminal vesicles & base of the urinary bladder; bloodstream (bones, particularly the axial skeleton; viscera); lymph - Bony metastases are osteoblastic; bones commonly involved are lumbar spine, proximal femur, thoracic spine & ribs - Lymphatic spread occurs in the obturator nodes, perivesical, hypogastric, iliac, presacral & paraaortic nodes - micro: adenocarcinomas with well-defined gland patterns; glands are lined by single uniform layer of cuboidal or low columnar epithelium - Neoplastic glands are crowded, lacks branching & papillary infolding; cytoplasm ranges from pale to clear to amphophilic appearance; nuclei is large with one or more large nucleoli - Uncommon mitotic figures - Histologic findings specific for prostate cancer: perineural invasion basal cell absent in prostate cancer High-Grade Prostatic Intraepithelial Neoplasia (PIN) Consist of benign glands with intra-acinar proliferation of cells showing nuclear anaplasia Consists of more widely separated, larger branching glands with papillary infolding Glands are surrounded by patchy layer of basal cells & intact basement membrane Lines of Evidence that Link High-Grade PIN to Invasive Cancer Both high-grade PIN & cancer predominate in the peripheral zone prostates with cancer have higher frequency & greater extent of high-grade PIN high-grade PIN is often seen in proximity to cancer many of the molecular changes seen in invasive cancer are also present in PIN Grading and Staging: Gleason System FIVE GRADES Grade 1 – most well-differentiated tumors; neoplastic glands are uniform & round & packed into well-circumscribed nodules Grade 5 – show no glandular differentiation; tumor cells infiltrate the stroma in the form of cords, sheets & nests other grades fall in between - Most tumors contain more than one pattern, a primary grade is assigned to the dominant pattern & secondary grade to the subdominant pattern; the two are added to obtain a combined Gleason grade or score - Gleason score of 2 (1+1) : most well-differentiated tumors - Gleason score of 10 (5+5): least-differentiated tumors Gleason score of 2 to 4: well-differentiated cancer; found in small tumors within the transition zone Gleason score of 5 to 6: intermediate-grade cancer; treatable cancer detected on needle biopsy Gleason score of 7: moderately to poorly differentiated cancer Gleason score of 8 to 10: high-grade cancer; advanced cancers that are unlikely to be curable STAGING OF PROSTATIC CANCER: TNM SYSTEM Stage T1 – refers to cancer found incidentally either on trans-urethral resection done for BPH symptoms (T1a & T1b depending on the extent & grade); or on needle biopsy, performed for elevated serum PSA levels (stage T1c) Stage T2 – organ-confined cancer Stage T3a and T3b – tumors show extraprostatic extension with & without seminal vesicle invasion respectively Stage T4 – direct invasion of contiguous organs CLINICAL COURSE • most patients with stage T1a cancer do not show evidence of progressive disease when followed for > 10 years • 5% to 25% of patients do develop local or distant spread; common in younger patients (< 60 years) • Stage T1b lesions are more ominous, 30% to 50% can be expected to progress in 5 years, with mortality of 20% if left untreated • Prostate-specific antigen (PSA) – used in the diagnosis & management of prostate cancer; elevated levels occur in association with localized as well as advanced cancer - is organ-specific but not cancer specific - increase level seen in BPH, prostatitis, infarct, instrumentation of the prostate & ejaculation - 20% to 40% of patients with organ-confined prostate cancer have a PSA value of 4.0 ng/mL • Localized prostate cancer: radical prostatectomy, external beam radiotherapy or interstitial radiotherapy • Advanced metastatic prostate cancer: endocrine therapy by depriving he tumor cells of testosterone (orchiectomy or administration of synthetic agonists of luteinizing hormone-releasing hormone); radiotherapy Miscellaneous Tumors and Tumor-like Conditions Ductal adenocarcinoma – arising from peripheral ducts or periurethral ducts (hematuria & urinary obstructive symptoms); poor prognosis Squamous carcinoma/ adenosquamous carcinoma of the prostate – develops either following hormone therapy or de novo Colloid carcinoma – contains abundant mucinous secretions Small cell cancer – most aggressive & rapidly fatal variant of prostate cancer Urothelial cancer – most common tumor to secondarily involve the prostate URETERS CONGENITAL ANOMALIES Double ureters – associated with 1. double renal pelves 2. anomalous development of large kidney with partially bifid pelvis terminating in separate ureters Ureteropelvic junction obstruction - seen in infants & children, common in boys; left ureter - most common cause of hydronephrosis in infants & children - in adults, more common in women & most often unilateral Diverticula – saccular outpouchings of the ureteral wall - uncommon; asymptomatic - importance: pockets of stasis and secondary infections Dilation (hydroureter) – congenital hydroureter is due to neurogenic defect in innervation of the ureteral muscle Megaloureter –massive enlargement of ureter due to a due to functional defect of ureteral muscle - if untreated, will result to hydronephrosis & decreased renal function INFLAMMATIONS Ureteritis – component of UTI - morphology: lymphocyte accumulation in the subepi- lium; slight elevations of the mucosa producing fine granular mucosal surface (ureteritis follicularis : 1-5 mm mucosal cysts (ureteritis cystica); cysts may aggregate to form small, grapelike clusters. TUMOR AND TUMOR-LIKE LESIONS Benign tumors – mesenchymal origin 1. Fibroepithelial polyp – small mass projecting into the lumen; presents as loose, vascularized connective tissue mass beneath the mucosa 2, Leiomyomas Primary malignant tumor – rare; majority are transitional cell CA; cause obstruction of ureteral lumen; multiple & occur concurrently with bladder or kidney CA OBSTRUCTIVE LESIONS Sclerosing Retroperitoneal Fibrosis – characterized by fibrous proliferative inflammatory process encasing the retroperitoneal structures causing hydronephrosis - histo: inflammatory fibrosis marked by lymphocytic infiltrates often with germinal centers, plasma cells & eosinophils