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276 Cards in this Set

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  • Back
1. What are the EGFR antagonists?
1. Gefitinib
2. Erlotinib, Lapatinib
3. Cetuximab
4. Trastuzumab, Pertizumab
2. Gefitinib
MOA: Reversible inhibitor of the EGFR (ErbB1) cytoplasmic tyrosine kinase domain; competes w/ATP binding to the kinase domain. Inhibitor of EFGR.

PURPOSE: Nonsmall cell lung CA

ADVERSE: Interstitial lung disease, corneal erosion, rash, diarrhea

CONTRA: Hypersensitivity to gefitinib

NOTES: More favorable response in pts with bronchoalveolar cell CA
3. What types of mutations have an increased sensitivity to gefitinib?
Common activating mutations were found in the kinase domain of the EGFR, including L858R and in-frame deletions spanning positions 746 and 753.

These mutations enhance tyrosine kinase activity in response to EGF and increase sensitivity to gefitinib.
4. Erlotinib
MOA: Erlotinib is a reversible inhibitor of the EGFR (ErbB1) cytoplasmic tyrosine kinase domain; competes w/ATP binding to the kinase domain

PURPOSE: Nonsmall cell lung CA; pancreatic CA

ADVERSE: MI, GI hemorrhage, DVT, microangiopathic hemolytic anemia, elevated LFT's, stroke, conjunctivitis, keratitis, rash, diarrhea

CONTRA: Hypersensitivity

NOTES: ***Erlotinib has a statistically greater survival benefit compared to gefitinib.
5. Lapatinib
MOA: Lapatinib is an inhibitor of EGFR and ErbB2, and is under development.

PURPOSE: Nonsmall cell lung CA; pancreatic CA

ADVERSE: MI, GI hemorrhage, DVT, microangiopathic hemolytic anemia, elevated LFT's, stroke, conjunctivitis, keratitis, rash, diarrhea

CONTRA: Hypersensitivity
6. Cetuximab
MOA: Cetuximab is a chimeric mouse/human IgG1 monoclonal antibody that binds EGFR (ErbB1) w/high specificity and affinity greater than EGF or TGF-alpha

PURPOSE: Colorectal CA; head and neck CA

ADVERSE: Cardiac arrest, leukopenia, renal failure, interstitial lung disease, pulmonary embolism, infection; rash, diarrhea, hypomagnesemia, gastrointestinal disturbance, asthenia, headache

CONTRA: Hypersensitivity

NOTES: ***Improved response rates in EGFR-expressing colorectal CA w/combined with irinotecan; ***Development of rash is predictive of tumor response.
7. Trastuzumab
MOA: Trastuzumab is a monoclonal antibody directed against ErbB2 (HER-2). Trastuzumab down-regulates HER-2 and thereby disurptes its signaling.

PURPOSE: Breast CA w/HER2 overexpression

ADVERSE: Cardiotoxicity, nephrotic syndrome, interstitial pneumonia; diarrhea, anemia, leukopenia

CONTRA: Hypersensitivity

NOTES: Treatment w/trastuzumab in the adjuvant setting enhances the efficacy of chemotherapy and reduces rates of recurrance.
8. What is pertuzumab?
Pertuzumab is another novel antibody under development. This agent binds to an epitope on HER-2 different from the epitope recognized by trastuzumab, and sterically hinders the association of HER-2 w/other ErbB family members.

Since HER-2 is one of the major dimerization partners used by this family of growth factor receptors, inhibition by pertuzumab is proposed to disrupt signaling by all EGFR family members and may be effective at lower levels of HER-2 expression.
9. What is imatinib mesylate?
Imatinib mesylate is a small molecule tyrosine kinase inhibitor that was initially developed as a 2-phenylaminopyrimidine derivative specific for PDGFR. Imatinib was subsequently found to be a potent inhibitor of EBL kinases, including the BCR-ABL fusion protein generated as a result of the t(9;22) chromosomal translocation (Philly) found in CML.

***Imatinib mesylate is the canonical example of a targeted therapeutic agent, b/c BCR-ABL is uniquely expressed by leukemic cells and is essential for their survival.
10. Imatinib mesylate
MOA: Small molecule tyrosine kinase inhibitor active against ABL kinases (including BCR-ABL fusion protein, c-KIT, and PDGFR)

PURPOSE: CML w/Philly chromosome, GIST with CD117, idiopathic hypereosinophilic syndrome

ADVERSE: Edema, myelosuppression, hepatotoxicity, nausea, muscle cramps, diarrhea, rash

CONTRA: Hypersensitivity

NOTES: Hematologic and cytogenetic response (disappearance of Philly chromosome) is observed in a large fraction of pts w/chronic phase CML; molecular response (disappearance of BCR-ABL) is observed in a smaller fraction.
11. What is idiopathic hypereosinophilic syndrome?
The idiopathic hypereosinophilic syndrome, as well as a variant of systemic mastocytosis w/eosinophilia, is characterized by the expression of the FIPL1-PDGFRA fusion protein, which is generated by an interstitial chromosomal deletion and results in constitutive signaling through PDGFRA.

Inhibition of PDGFRA by treatment with imatinib mesylate has been a successful therapeutic approach in both conditions.
12. Dasatinib
MOA: Dasatinib is a dual SRC-ABL kinase inhibitor that binds to the ATP binding site in ABL irrespective of the conformational status of the activation loop.

Dasatinib has significantly greater efficacy than imatinib mesylate against wild type BCR-ABL, and it inhibits the activity of most clinically relevant imatinib mesylate-resistant BCR-ABL isoforms, w/the exception of the T315I mutation.
13. Nilotinib
MOA: Nilotinib substitutes alternative binding groups for the N-methylpiperazine group.

Nilotinib also has significantly greater efficacy than imatinib mesylate against wild type BCR-ABL, and it inhibits the activity of most clinically relevant imatinib mesylate-resistant BCR-ABL isoforms, w/the exception of the T315I mutation
14. What are the inhibitors of RAS/MAP kinase pathways?
Farnesylation of RAS is essential for its association w/the plasma membrane and subsequent activation.

A number of farnesyltransferase inhibitors (FTI's) have been developed that inhibit RAS farnesylation.

FTIs that have been tested clinically include tipifarnib and lonafarnib, as well as sorafenib.
15. Tipifarnib and lonafarnib
MOA: Tipifarnib and lonafarnib inhibit farnesyltransferase, which is important for farnesylation of RAS and recruitment of RAS to the plasma membrane

PURPOSE: Relapsing or refractory AML
16. Sorafenib
MOA: Initially developed as a C-RAF inhibitor, sorafenib demonstrates high inhibitory activity on both wild-type and mutant B-RAF. Also inhibits VEGFR-2 and PDGRF-beta

PURPOSE: Renal cell CA

ADVERSE: Cardiovascular disease, erythema multiforme, hemorrhage, thromboembolic disorder, acute renal failure; hypertension, alopecia, hand-foot rash and pain due to cytotoxic therapy, rash, GI disturbance, elevated amylase and lipase levels, depressed blood cell counts, neuropathy

CONTRA: Hypersensitivity

NOTES: Significant activity against melanoma cell lines that contain activating B-RAF mutations.
17. What are the mTOR inhibitors?
Signaling via the PI3K/AKT pathway leads to downstream activation of the mammalian target of rapamycin (mTOR).

mTOR is a serine-theronine kinase that regulates multiple cellular functions, including cell growth and proliferation, via activation of translation. Dysregualted mTOR activity is seen in a wide variety of malignancies.

These inhibitors include Rapamycin (sirolimus); temsirolimus, and everolimus.
18. Rapamycin (sirolimus)
MOA: m-TOR is a serine-threonine kinase that regulates cell growth and proliferation via activation of translation; rapamycin binds to FKBP12, and the rapamycin-FKBP12 complex binds to mTOR and inhibits its activity

PURPOSE: Prophylaxis for renal transplant rejection

ADVERSE: DVT, PE, pancytopenia, hepatotoxicity, interstitial lung disease; hypertension, peripheral edema, asthenia, arthralgia

NOTES: In addition to inhibiting mTOR, rapamycin also blocks downstream targets of mTOR such as cyclin D1, c-MYC, the antiapoptotic protein DAD, and HIF-1.
19. What about Temsirolimus and Everolimus?
Temsirolimus and everolimus are soluble ester analogues of rapamycin that demonstrate dose-dependent inhibitor of tumor cell growth in vitro.

Temsirolimus has shown evidence of activity in several phase II clinical studies in renal cell CA, breast CA, and mantle cell NHL.

Toxicities have included skin rash, mucositis, thrombocytopenia, and leukopenia.
20. What is Bortezomib?
The small molecule bortezomib, a dipeptide w/a linked boronate moiety, targets w/high affinity and specificity an active site N-terminal theronine residue w/in the 20S catalytic subunit of the proteasome. Bortezomib induces growth inhibition and apoptosis of tumor cells w/relatively few toxic effects on normal cells.

Clinically, the effects of bortezomib are reversible, requiring IV dosing on a 2x weekly schedule.
21. Bortezomib
MOA: Inhibits an active site N-terminal threonine residue w/in the 20S catalytic subunit of the proteasome

PURPOSE: Multiple myeloma, Mantle cell lymphoma

ADVERSE: Heart failure, neutropenia, thrombocytopenia, neuropathy, hypotension, rash, GI disturbance, arthralgia

CONTRA: Hypersensitivity to bortezomib, boron, or mannitol

NOTES: B/c of its relatively modest adverse effects, bortezomib is incorporated into combination regimens for primary therapy of multiple myeloma, with good response rates
22. Bevacizumab
MOA: Bevacizumab is a recombinant humanized mouse monoclonal IgG1 antibody directed against VEGF-A, one of the major proangiogenic VEGF family members.

PURPOSE: Metastatic colorectal CA; metastatic breast CA; nonsmall cell lung CA

ADVERSE: Arterial thromboembolism, hypertensive crisis, impaired wound healing, GI perforation, nephrotic syndrome; neuropathy, dizziness, headache, GI disturbance

CONTRA: Hypersensitivity

NOTES: Clinical trials are ongoing to determine efficacy in other solid tumors such as ovarian and pancreatic CA
23. Sunitinib
MOA: Inhibits VEGFR-1, VEGFR-2, and PDGFR

PURPOSE: Renal cell CA, GIST

ADVERSE: Left ventricular dysfunction, anemia, hemorrhage, neutropenia, thrombocytopenia, lymphopenia; yellow skin, inflammation of mucous membrane, neuropathy, gastrointestinal disturbance

CONTRA: Hypersensitivity
24. Vatalanib
Vatalanib inhibits VEGFR-1 and VEGFR-2, and is under investigation in metastatic colorectal CA
25. What is thalidomide?
Thalidomide is a synthetic glutamic acid derivative that was found to have sedative and antiemetic properties and was marketed as a treatment of morning sickness in pregnant women. However, it was found to be teratogenic, and it was withdrawn.

Thalidomide was subsequently shown to have imunomodulatory properties, inhibiting the synthesis of TNF-alpha, and demonstrating efficacy in the Tx of erythema nodosum leprosum. It has also been shown that thalidomide inhibits basic fibroblast growth factor (bFGF)-induced angiogenesis.
26. Thalidomide
MOA: Thalidomide is an immunomodulatory drug that inhibits basic fibroblast growth factor (bFGF)-induced angiogenesis and the synthesis of TNF-alpha; also co-stimulates T cells

PURPOSE: Multiple myeloma; Erythema nodosum leprosum

ADVERSE: Teratogenesis, thrombotic disorder, neutropenia, leukopenia, Stevens-Johnson syndrome; Peripheral neuropathy, edema, hypocalcemia, constipation, somnolence

CONTRA: Pregnancy, women capable of becoming pregnant, males not using condom

NOTES: Combo of thalidomide with dexamethasone is a standard first-line regimen for multiple myeloma, w/response rates of 60-70%.
27. Lenalidomide
MOA: Lenalidomide is an analogue of thalidomide w/enhanced inhibition of TNF-alpha and improved T-cell costimulatory properties, while maintaining anti-angiogenic activity

PURPOSE: Multiple myeloma; Myelodysplastic syndrome

ADVERSE: Same as thalidomide, except for lower incidence of thrombosis, neuropathy, constipation, and somnolence

CONTRA: Pregnancy, women capable of becoming pregnant, males not using condom

NOTES: *Combo of lenalidomide w/dexamethasone has response rates of 90% in multiple myeloma.
28. What are the names of the tumor specific monoclonal antibodies and other recombinant proteins?
1. Rituximab: anti-CD20
2. Tositumomab: anti-CD20
3. Ibritumomab: anti-CD20
4. Alemtuzumab: anti-CD52
5. Denileukin diftitox: fusion protein of diphtheria toxin and IL-2
6. Gemtuzumab: conjugate of anti-CD33 antibody and calichheamicin (antitumor antibiotic)
29. Which monoclonal antibodies are used for B-cell NHL?

T-cell NHL?
Rituximab, tositumab, and ibritumomab are used for B cell NHL.

Denileukin diftitox is used for T cell NHL
30. Tx of CLL?

Tx of AML?
Alemtuzumab is used for CLL

Gemtuzumab is used for AML.
31. What are the adverse effects of these tumor specific monoclonal antibodies and other recombinant proteins?
ADVERSE: Significant immunosuppression (including the risk of developing opportunistic bacterial, fungal, and viral infections), hypersensitivity, anaphylactoid reaction related to chimeric antibody ; hematologic abnormalities, infusion reactions.
32. What is hypospadias and epispadias?
Malformation of the urethral groove and urethral canal may create abnormal openings either on the ventral surface of the penis (hypospadias) or on the dorsal surface (epispadias).

Although more freq w/epispadias, either of these two anomalies may be associated w/failure of normal descent of the testes with malformations of the urinary tract.
33. Which is more common - hypospadias or epispadias?
Hypsopadias, the more common of the two, occurs in approx 1/300 live births. Even when isolated, these urethral defects may have clinical significance b/c often the abnormal opening is constricted, resulting in urinary tract obstruction and an increased risk of ascending UTIs.

These lesions are possible causes of sterility in men.
34. What is phimosis?
When the orifice of the prepuce is too small to permit its normal retraction, the condition is designated phimosis. Such an abnormally small orifice may result from anomalous development but it is more freq the result of repeated attacks of infection that cause scarring of the preputial ring.

Phimosis is important b/c it interferes with cleanliness and permits the accumulation of secretions and detritus under the prepuce, favoring the development secondary infections and possibly carcinoma.
35. What is paraphimosis?
When a phimotic prepuce is forcibly retracted over the glans penis, marked constriction and subsequent swelling may block the replacement of the prepuce, creating paraphimosis.

Not only is this condition extremely painful, but it also may be a potential cause of urethral constriction and serious acute urinary retention.
36. What is condyloma acuminatum?
Condyloma acuminatum is a benign tumor caused by HPV types 6 or 11. It is related to the common wart, and may occur on any moist mucocutaneous surface of the external genitals in either sex.
37. What is the morphology of condyloma acuminatum?
Condylomata may occur on the external genitalia or perineal areas. On the penis, these lesions occur most often about the coronal sulcus and inner surface of the prepuce.

They consist of single or multiple sessile or pedunculated, red papillary excrescences that vary from 1 mm to several mm in diameter. Histologically, a branching, villous, papillary CT stroma is covered by epithelium that may have considerable superficial hyperkeratosis and thickening of the underlying epidermis (acanthosis).

The normal orderly maturation of the epithelial cells is preserved. Clear vacuolization of the prickle cells (koilocytosis), characteristic of HPV infection, is noted in these lesions.
38. What are the two distinct lesions of the penis that display histologic features of carcinoma in situ?
Bowen disease and bowenoid papulosis.

All these lesions have a strong association w/infection by HPV, most commonly type 16.
39. What is Bowen disease?
Bowen disease occurs in the genital region of both men and women, usually in those over the age of 35. In men, it is prone to involve the skin of the shaft of the penis and the scrotum.

Grossly, it appears as a solitary, thickened, gray-white, opaque plague with shallow ulceration and crusting.
40. What is Erythroplasia of Queyrat?
Bowen disease can also manifest on the glans and prepuce as single or multiple shiny red, sometimes velvety plaques, where it is referred to as Erthroplasia of Queyrat.
41. What is the morphology of Bowen disease?
Histologically, the epidermis shows proliferation w/numerous mitoses, some atypical. The cells are markedly dysplastic w/large hyperchromatic nuclei and lack of orderly maturation.

***Nevertheless, the dermal-epidermal border is sharply delineated by an intact basement membrane.***
42. What are the clinical features of Bowen disease?
Over the span of years, Bowen disease may transform into infiltrating squamous cell CA in approx 10% of patients. Another feature that is said to be associated w/this disease is the occurrence of visceral CA in approx 1/3 of the pts.
43. What is bowenoid papulosis?
Bowenoid papulosis occurs in sexually active adults. Clinically, it differs from Bowen disease by the younger age of pts and the presence of multiple (rather than solitary) pigmented (reddish brown) papular lesions.

In some cases, the lesions may be verrucoid and readily mistaken for condyloma acuminatum. Histologically, bowenoid papulosis is indistinguishable from Bowen disease and is also related to HPV 16.

***In contrast to Bowen disease, bowenoid papulosis virtually never develops into an invasive CA, and in many cases, it spontaneously regresses.
44. What is the prevalence of squamous cell CA of the penis?
SCC of the penis is an uncommon malignancy in the US; by contrast, the incidence ranges from 10-20% of male malignancies in some parts of Asia, Africa, and South America. A striking correlation exists btwn the practice of circumcision and the occurrence of penile cancer. Circumcision confers protection.

It is postulated that circumcision is associated with better genital hygiene which in turn reduces exposure to carcinogens that may be concentrated in smegma and decreases the likelihood of infection with potentially oncogenic HPV.
45. What is the pathogenesis of squamous cell CA of the penis?
HPV DNA can be detected in the cancer cells in approx 50% of pts. HPV type 16 is the most freq culprit, but type 18 is also implicated.

CA in situ (Bowen disease), the presumed precursor lesion of invasive SCC of the penis, has a much stronger association with HPV. This disparity suggests that infection w/HPV is not sufficient for transformation that it probably acts in concert with other carcinogenic influences. These may include carcinogens in cigarette smoke.
46. What are the 2 morphologic patterns of squamous cell CA of the penis?
Papillary and flat.

The 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. With progression, an ulcerated papule develops.
47. What is the morphology of squamous cell CA of the penis?
Squamous cell CA of the penis usually begins on the glans or inner surface of the prepuce near the coronal glans.

Histologically, both the papillary and the flat lesions are squamous cell CAs with varying degrees of differentiation.
48. What is verrucous carcinoma of the penis?
Verrucous CA is an uncommon, well-differentiated variant of squamous cell CA that has low malignant potential. These tumors are locally invasive, but they rarely metastasize.

As the name indicates, these tumors have a verrucous (papillary) appearance, similar to condylomata acuminata, but they are larger than the usual condylomata.

***In contrast to condylomata, however, cerrucous CAs can invade the underlying tissues.***
49. What is the clinical course of squamous cell CA of the penis?
Invasive squamous cell CA of the penis is a slowly growing, locally invasive lesion that often has been present for a year or more before it is brought to medical attention.

The lesions are not painful until they undergo secondary ulceration and infection.

Freq they bleed. Metastases to inguinal and iliac lymph nodes characterize the early stage, but widespread dissemination is extremely uncommon until the lesion is far advanced.
50. What is cryptorchidism?
Cyptorchidism is synonymous w/undescended testes and is found in approx 1% of 1 year old boys. This anomaly represents a complete or incomplete failure of the intra-abdominal testes to descend into the scrotal sac. It usually occurs as an isolated anomaly but may be accompanied by other malformations of the genitourinary tract, such as hypospadias.
51. What is the pathogenesis of cryptorchidism?
Although tests may be arrested anywhere in their pathway of descent, defects in transabdominal descent are uncommon. In most pts, the undescended testis is palpable in the inguinal canal.

Despite the fact that testicular descent is controlled by hormonal factors, cryptorchidism is only rarely associated w/hormonal disorders.

It may be one of several congenital defects in chromosomal disorders, such as trisomy 13.
52. What is the morphology of cryptorchidism?

Cryptorchidism is unilateral in most cases, but can be bilateral in 25%. Histologic changes in the malpositioned testis begin as early as 2 years of age.

They are characterized by an arrest in the development of germ cells associated with marked hyalinization and thickening of the basement membrane of the spermatic tubules. Eventually the tubules appear as dense cords of hyaline CT outlined by prominent basement membranes. There is concomitant increase in interstitial stroma.
53. What is the morphology of cryptorchidism?

B/c Leydig cells are spared, they appear to be prominent. As might be expected with progressive tubular atrophy, the cryptorchid testis is small in size and firm in consistency, owing to fibrotic changes.

Histologic deterioration, leading to a paucity of germ cells, has also been noted in the contralateral (descended) testis in pts w/unilateral cryptorchidism, supporting a hormonal basis for the development of this condition.
54. What are the clinical features of cryptorchidism?
When the testis lies in the inguinal canal, it is particularly exposed to trauma and crushing against the ligaments and bones. A concomitant inguinal hernia accompanies such malposition of the testis in about 10-20% of cases. From the morphologic changes, it is apparent that bilateral cryptorchidism may result in sterility.

Infertility, however, is also noted in a significant number of cases with uncorrected unilateral cryptorchidism b/c the contralateral descended testis may also be deficient in germ cells. In addition, the undescended testis is at a greater risk of developing testicular CA than is the descended testis.
55. What are the 8 causes of atrophy of the scrotal testis?
1. Progressive atherosclerotic narrowing of the blood supply in old age
2. The end stage of an inflammatory orchitis, whatever the etiologic agent
3. Cryptorchidism
4. Hypopituitarism
5. Generalized malnutrition or cachexia
6. Irradiation
7. Prolonged administration of female sex hormones
8. Exhaustion atrophy, which may follow the persistent stimulation produces by high levels of follicle-stimulating pituitary hormone
56. What are the morphologic changes associated w/atrophy of the scrotal testis?
These changes follow the pattern already described for cryptorchidism. When the process is bilateral, as it freq is, sterility results. Atrophy or sometimes improper development of the testes occasionally occurs as a primary failure of genetic origin, such as Klinefelter syndrome.
57. What are the findings associated with decreased fertility?
These include hypospermatogenesis, maturation arrest, and findings associated with vas deferens obstruction. In some instances a specific cause of the testicular injury can be found, and if it can be removed prior to the development of atrophy, testicular function can be restored.
58. Where do gonorrhea, tuberculosis and syphilis arise in the male genitalia?
*It is classically taught that gonorrhea and tuberculosis almost invariably arise in the epididymis, whereas syphilis affects the testis first.
59. What is epididymitis and orchitis?
Epididymitis and possible subsequent orchitis are commonly related to infections of the urinary tract (cystitis, urethritis, genitoprostatitis), which presumably reach the epididymis and the testis thru either the vas deferens or the lymphatics of the spermatic cord.
60. What is the pathogenesis of epididymitis and orchitis?
The cause varies with the age of the pt. Although uncommon in children, epididymitis in childhood is usually associated w/a congenital genitourinary abnormality and infection with Gram negative rods.

In sexually active men younger than 35, Chlamydia trachomatis and N. gonorrhoeae are the most freq culprits.

In men older than age 35, the common urinary tract pathogens, such as E. coli and Pseudomonas are responsible for most infections.
61. What is the morphology of epididymitis?
The bacterial invasion sets up a nonspecific acute inflammation characterized by congestion, edema, and infiltration by neutrophils, macrophages, and lymphocytes. Although the infection, in the early stage, is most or less limited to the interstitial CT, it rapidly extends to involve the tubules and may progress to frank abscess formation or complete suppurative necrosis of the entire epididymis.

Usually it can spread to the testis, which is often followed by fibrous scarring, which in many cases leads to sterility. Usually, the interstitial cells of Leydig are not totally destroyed, so sexual activity is not disturbed.
62. What is granulomatous (autoimmune) orchitis?
Among middle aged men, a rare cause of unilateral testicular enlargement is nontuberculous, granulomatous orchitis. It usually presents as a moderately tender testicular mass of sudden onset sometimes associated with fever. It may appear insidiously, however, as a painless testicular mass mimicking a testicular tumor, hence its importance.

Although an autoimmune basis is suspected, the cause of these lesions remains unknown
63. What is the morphology of granulomatous orchitis?
Histologically, the orchitis is distinguished by granulomas that are seen restricted w/in spermatic tubules. The lesions closely resemble tubercles but differ in that the granulomatous reaction is present diffusely throughout the testis and is confined to the seminiferous tubules.
64. Specific inflammations of gonorrhea?
Extension of infection from the posterior urethra to the prostate to the seminal vesicles and then to the epididymis is the usual course of a neglected gonococcal infection.

Inflammatory changes similar to those described in the nonspecific infections occur, with the development of frank abscesses in the epididymis, resulting in extensive destruction of this organ. In the more neglected cases, the infection can then spread to the testis and produce a suppurative orchitis.
65. What about mumps and orchitis?
Mumps is a systmic viral disease that most commonly affects school age children. Testicular involvement is extremely uncommon in this age group.

In postpubertal males, however, orchitis may develop and has been reported in 20-30% of male pts. Most often, the acute interstitial orchitis develops about 1 week after onset of swelling of the parotid glands. Rarely, cases of orchitis precede the parotitis or may be unaccompanied by parotid gland involvement.
66. Tuberculosis and orchitis?
*Tuberculosis almost invariably begins in the epididymis and may spread to the testis.***

In many of these cases, there is associated tuberculous prostatitis and seminal vesiculitis, and it is believed that epididymitis usually represents a secondary spread from these other involvements of the genital tract. The infeciton invokes the classic morphologic reactions of caseating granulomatous inflammation that are characteristic of tuberculosis elsewhere?
67. Syphilis and orchitis?
The testis and epididymis are affected in both acquired and congenital syphilis, ***but almost invariably, the testis is involved first by the infection.***

In many cases, the orchitis is not accompanied by epididymitis. The morphologic pattern of the reaction takes 2 forms; the production of gummas or a diffuse interstitial inflammation characterized by edema and lymphocytic and plasma cell infiltration w/the characteristic hallmark of all syphilitic infections (i.e., obliterative endarteritis w/perivascular cuffing of lymphocytes and plasma cells).
68. What is testicular torsion?
Twisting of the spermatic cord may cut off the venous drainage and the arterial supply to the testis. Usually, however, the thick-walled arteries reamin patent, so intence vascualr engorgement and venous infarction follow. There are 2 types of testicular torsion - neonatal torsions and adult torsions.

In contrast to neonatal torsion, adult torsion results from a bilateral anatomic defect in which the testis has increased mobility, giving rise to what is termed the bell clapper abnormality. It often occurs w/o any inciting injury, sudden pain heralding the torsion may even occur during sleep.

***Torsion must be corrected by surgical intervention w/in approx 6 hours after the onset of torsion.
69. What is the morphology of testicular torsion?
Depending on the duration of the process, the morphologic changes range from intense congestion to widespread extravasation of blood into the interstitial tissue of the testis and epididymis.

Eventually, hemorrhagic infarction of the entire testis occurs. In the late stages, the testis is markedly enlarged and is converted virtually into a sac of soft, necrotic, hemorrhagic tissue.
70. What is the most common benign paratesticular tumor?
The most common benign paratesticular tumor is adenomatoid tumor.

Although these lesions are mesothelial in nature, they are not referred to as mesotheliomas, in order to distinguish them from other mesothelial lesions that occur at this site.
71. What is the morphology of the adenomatoid tumor?
Adenomatoid tumors are usually small nodules that typically occur near the upper pole of the epididymis. Although they are grossly well circumbscribed, microscopically they may be minimally invasive into the surrounding tissue, including the adjacent testis.

*The importance of this lesion is that it is one of the few benign tumors seen near the testis.
72. What is the most common malignant paratesticular tumor?
The most common malignant paratesticular tumors located at the distal end of the spermatic cord are rhabdomyosarcomas in children and liposarcomas in adults.
73. What is the prevalence of germ cell tumors?
Approx 8000 cases of testicular tumors are Dx per year in the US. In the 15-35 age group, when these neoplasms have a peak incidence, they constitute the most common tumor of men and cause approx 10% of all CA deaths. In the US, these tumors are much more common in whites than in blacks (ratio 5:1).
74. What are germ cell tumors?
Germ cells are multipotential, and once they become cancerous, they are not inhibited by their lines of differentiation. Testicular germ cell tumors may be divided into two categories on the basis of whether they are composed of a single histologic pattern or more than one.

Tumors w/a single histologic pattern constitute about 40% of all testicular neoplasms. In approx 60% of the tumors, there is a mixture of 2 or more of the histologic patterns.
75. What are the germ cell tumors in the mixed group?
Most tumors in this group originate from intratubular germ cell neoplasia (ITGCN). ITGCN is seen adjacent to all germ cell tumors in adults except for spermatocytic seminoma and epidermoid and dermoid cysts. With rare exceptions, it is also not seen in pediatric tumors (teratomas, yolk sac tumors).

Untreated ITGCN progresses to invasive germ cell tumor in approx 50% of cases over 5 years. If it is identified, it is treated by low dose radiotherapy.
76. ITGCN is encountered with a high freq in which conditions?
Listed in order of increasing risk:
1. Crytorchidism
2. Prior germ cell tumors
3. Strong family history of germ cell tumor
4. Androgen insensitivity syndrome
5. Gonadal dysgenesis syndrome
77. Neoplastic germ cells may differentiate to give rise to...?
Neoplastic germ cells may differentiate along gonadal lines to give rise to seminoma or transform into a totipotential population that gives rise to nonseminomatous tumors. Such totipotnetial cells may remain largely undifferentiated to form embryonal CA or may differentiate along extraembryonic lines to form yolk sac tumors or choriocarcinomas.
78. Which type of testicular tumor may act as precursors from which other forms of testicular germ cell tumors originate?
Seminomas. This view is supported by the fact that cells that form intratubular germ cell neoplasias (the presumed precursors or all types of germ cell tumors) share morphologic and molecular characteristics with tumor cells in seminomas.
79. What is the most important distinction in germ cell tumors?
From a clinical standpoint, the most important distinction in germ cell tumors is between seminomas and nonseminomatous tumors.
80. What are 3 predisposing influences in the pathogenesis of germ cell tumors?
1. Cryptorchidism
2. Testicular dysgenesis
3. Genetic factors

***The higher the location of the undescended testicle (intra-abdominal vs. inguinal), the greater the risk of developing CA.
81. What genetic change is associated in all germ cell tumors?
An isochromosome of the short arm of chromosome 12, i(12p), is found in virtually all germ cell tumors, regardless of their histologic type. In the approx 10% of cases in which i(12p) is not detected, extra genetic material derived from 12p is found on other chromosomes.

The dosage of genes located on 12p is critical for the pathogenesis of germ cell tumors, and several candidate genes have been identified, including DAD-R, that prevents apoptosis.
82. What is a seminoma?
Seminomas are the most common type of germinal tumor (50%) and the type most likely to produce a uniform population of cells. They almost never occur in infants; they peak in the thirties. An identical tumor arises in the ovary, where it is called dysgerminoma.
83. What is the morphology of a seminoma?

Seminomas produce bulky masses, sometimes 10x the size of the normal testis. The typical seminoma has a homogeneous, gray-white, lobulated cut surface, usually devoid of hemorrhage or necrosis. In more than half of cases, the entire testis is replaced. Generally, the tunica albuginea is not penetrated, but occasionally, extension to the epididymis, spermatic cord, or scrotal sac occurs.
84. What is the morphology of a seminoma?

Microscopically, the typical seminoma presents of uniform cells divided into poorly demarcated lobules by delicate septa of fibrous tissue.

***The classic seminoma cell is large and round to polyhedral and has a distinct cell membrane; a clear or watery-appearing cytoplasm, and a large, central nucleus with one or two prominent nucleoli.***

Mitoses vary in freq. The cytoplasm contains varying amts of glycogen. Classic seminoma cells do not contain AFP or HCG. The tumor cells stain positively for placental ALKPHOS, and scattered cells may be keratin positive.
85. What about seminomas that contain syncytiotrophoblasts?
Approx 15% of seminomas contain syncytiotrophoblasts. In this subset of pts, serum HCG levels are also elevated, althoguh not to the extent seen in pts with choriocarcinoma. The amt of stroma in typical seminomas varies greates. Sometimes it is abundant. Usually, well-defined fibrous strands are present, creating lobules of neoplastic T lymphs, and in some tumors, granulomas.
86. What are anaplastic seminomas?
The term anaplastic seminoma is used by some to indicate greater cellular and nuclear irregularity w/more freq tumor giant cells and many mitoses. However, b/c "anaplastic seminoma" is not associated w/a worse prognosis when matched for stage w/classic seminoma, and is not treated differently, most authorities do not recognize this as a distinct entity.
87. What is a spermatocytic seminoma?
Although related by name to seminoma, spermatocytic seminoma is a distinctive tumor both clinically and histologically. It is one of the two variants of germ cell tumors that do not arise from an intratubular germ cell neoplasia, the other being teratomas of children.

Spermatocytic seminoma is an uncommon tumor, representing 1-2% of all testicular germ cell neoplasms.

The age of involvement is much later than for most testicular tumors: affected individuals are generally over 65. This is a slow growing tumor that rarely if ever produces metastases, hence, the prognosis is excellent.
88. What is the morphology of spermatocytic seminoma?
Grossly, spermatocytic seminoma tends to be larger than classic seminoma and presents w/a pale gray, soft, cut surface sometimes w/mucoid cysts.

Spermatocytic seminomas have 3 cell populations, all mixed: (1) medium sized cells which are most numerous, containing a round nucleus and eosinophilic cytoplasm; (2) smaller cells, with a narrow rim of eosinophilic cytoplasm resembling secondary spermatocytes; and (3) scattered giant cells , either uninucleate or multinucleate.
89. Why are they called spermatocytic seminoma?
In some intermediate sized cells, chromatin is similar to that seen in the meiotic phase of non-neoplastic spermatocytes (spireme chromatin), thus justifying the term spermatocytic seminoma.
90. What is an embryonal carcinoma?
Embryonal carcinomas occur mostly in the 20-30 year old age group. These tumors are more aggressive than seminomas.

Grossly, the tumor is smaller than seminoma and usually does not replace the entire testis. On cut surfaces, the mass is often variegated, poorly demarcated at the margins, and punctuated by foci of hemorrhage or necrosis. Extension through the tunica albuginea into the epididymis or cord is not infrequent.
91. What is the morphology of an embryonal carcinoma?
***Histologically, the cells grow in alveolar or tubular patterns, sometimes w/papillary convolutions***. Embryonal CAs lack the well formed glands w/basally situated nuclei and apical cytoplasm seen in teratomas.

*More undifferentiated lesions may present sheets of cells*.

The neoplastic cells have an epithelial appearance and are large and anaplastic, with hyperchromatic nuclei having prominent nucleoli. In contrast to seminoma, the cell borders are usually indistinct, and there is considerable variation in cell and nuclear size and shape. Mitotic figures and tumor giant cells are frequent.

***Within this background, syncytial cells containing HCG, AFP, or both may be detected.
92. What is a yolk sac tumor?
AKA infantile embryonal carcinoma or endodermal sinus tumor, the yolk sac tumor is of interest b/c it is the most common testicular tumor in infants and children up to 3 years of age, and in this age group, it has a very good prognosis.

In adults, the pure form of this tumor is rare; instead, yolk sac elements freq occur in combo w/embryonal CA.
93. What is the morphology of a yolk sac tumor?
Grossly, the tumor is nonencapsulated, and on cross section, it presents a homogeneous, yellow-white, mucinous appearance. ***Characteristic on microscopic exam is a lace-like (reticular) network of medium-sized cuboidal or elongated cells.*** In addition, papillary structures or solid cords of cells may be found.

In about 1/2 of tumors, structures resembling endodermal sinuses (Schiller-Duval bodies) may be seen; these consist of a mesodermal core w/a central capillary and a visceral and parietal layer of cells resembling primative glomeruli.
94. What is highly characteristic of a yolk sac tumor?
The presence of AFP in the tumor cells in highly characteristic.

Present w/in and outside the cytoplasm are eosinophilic, hyaline-like globules in which AFT and alpha1 antitrypsin can also be demonstrated.
95. What is a choriocarcinoma?
Choriocarcinoma is a highly malignant form of testicular tumor that is composed of both cytotrophoblastic and syncytiotrophoblastic cells. Identical tumors may arise in the placental tissue, ovary, or sequestered rests of totipotential cells (e.g., in the mediastinum or abdomen).

In its pure form, choriocarcinoma is rare, occurring in fewer than 1% of all germ cell tumors. Foci of choriocarcinoma are much more common in mixed patterns.
96. What is the morphology of a chroriocarcinoma?

Despite their aggressive behavior, pure ones are usually small lesions. ***Often they cause no testicular enlargement and are detected only as a small palpable nodule***.

B/c they are rapidly growing, they may outgrow their blood supply, and sometimes the primary testicular focus is replaced by a small fibrous scar, leaving only widespread metastases.
97. What is the morphology of a chroriocarcinoma?

Typically, these tumors are small, rarely larger than 5 cm in diameter. Hemorrhage and necrosis are extremely common. Histologically, the tumors contain 2 cells types; the syncytiotrophoblastic cell and cytotrophoblastic cells.
98. What is the difference between syncytiotrophoblastic cell and cytotrophoblastic cells?
The syncytiotrophoblastic cell is large and has many irregular or lobular hyperchromatic nuclei and an abundant eosinophilic vacuolated cytoplasm. HCG can be readily demonstrate in the cytoplasm of these cells.

The cytotrophoblastic cells are more regular and tend to be polygonal with distinct cell borders and clear cytoplasm; they grow in cords or masses and have an single, fairly uniform nucleus.
99. What is a teratoma?
The designation teratoma refers to a group of complex tumors having various cellular or organoid components reminiscent of normal derivatives from more than one germ layer. They may occur at any age.

Pure teratomas are fairly common in infants and children, second only in freq to yolk sac tumors.

In adults, pure teratomas are rare. As w/embryonal CAs, their freq in combination w/other histologic types is about 45%.
100. What is the morphology of teratomas?
Grossly, teratomas are usually large, ranging from 5-10 cm in diameter.

B/c they are composed of various tissues, the gross appearance is hetergeneous, with solid, sometimes cartilagionous and cystic areas. Hemorrhage and necrosis usually indicate admixture with embryonal carcinoma, choriocarcinoma, or both.
101. What are teratomas composed of?
Teratomas are composed of a heterogeneous, helter skelter collection of differentiated cells or organoid structures, such as 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, all embedded in a fibrous or myxoid stroma.

Elements may be mature or immature.
102. What about dermoid or epidermoid cysts in the testis?
Dermoid cysts and epidermoid cysts, common in the ovary, are rare in the testis. These cysts should not be considered teratomas, since they have a uniformly benign behavior regardless of the pts age.
103. What are teratomas with malignant transformation?
Rarely, non germ cell tumors may arise in a teratoma. These tumors are referred to as "teratoma w/malignant transformation", and they reveal malignancy in derivatives in one or more germ cell layers. Thus, there may be a focus of squamous cell CA, mucin-secreting adenocarcinoma, or sarcoma.

***The importance of recognizing a non-germ cell malignancy arising in a teratoma is that when the non-germ cell component spreads outside of the testis it does not respond to chemo and the only hope for cure lies in resection.***

These non germ cell malignancies have some of the same chromosome abnormalities (isochromosome 12p) as the germ cell tumors from which they arose.
104. What are the clinical features of teratomas?
In children, differentiated mature teratomas may be expected to behave as benign tumors, and almost all these pts have a good prognosis.

*In the postpubertal male, all teratomas are regarded as malignant and capable of metastatic behavior, regardless of whether the elements are mature or immature.*

Consequently, it is not critical to note histologic differentiation in a postpubertal male with a testicular teratoma.
105. What are mixed tumors?
About 60% of testicular tumors are composed of more than one of the pure patterns. Common mixtures include teratoma, embryonal CA, and yolk sac tumor; seminoma with embryonal CA; and embryonal CA with teratoma (teratocarcinoma).

In most instances, the prognosis is worsened by the inclusion of more aggressive elements.
106. What are the 2 categories of tumors of the testis?
1. Seminoma
2. Nonseminomatous germ cell tumors (NSGCT)
107. What are nonseminomatous germ cell tumors (NSGCT)?
NSGCT is an umbrella designation that includes tumors of one histologic type, such as embryonal cell CA, as well as those with more than one pattern.

Approx 60% of pts with NSGCT present with advanced clinical disease (stages 2 and 3). These tumors not only metastasize earlier than seminomas but also use the hematogenous route more freq. The rare pure choriocaricnoma is the most aggressive of the NSGCT (it spreads predominantly and rapidly by the bloodstream). Therefore, the lungs and liver are involved early in virtually every case.

Also, NSGCT's are relatively radioresistant.
108. What are the seminomas?
Seminomas tend to remain localized to the testis for a long time; approx 70% of pts present in stage 1. In contrast to NSGCT's, metastases from seminomas typically involve lymph nodes, with hematogenous spread occurring later in the course.

These tumors are extremely radiosensitive.
109. What are the features of mixed tumors as a group?
Although painless enlargement of the testis is a characteristic feature of germ cell neoplasm, any testicular mass should be considered neoplastic unless proved otherwise.

Biopsy of a testicular neoplasm is associated w/a risk of tumor spillage, which would necessitate excision of the scrotal skin in addition to orchiectomy.

Testicular tumors have a characteristic mode of spread. Lymph spread is common to all forms to testicular tumors, and in general, retroperitoneal para-aortic nodes are the first to be involved. Subsequent spread may occur to mediastinal and supraclavicular nodes. Hematogenous spread is primarily to the lungs, but liver, brain, and bones may also be involved.
110. What are the 3 clinical stages of testicular tumors?
Stage 1: Tumor confined to the testis, epididymis, or spermatic cord

Stage 2: Distant spread confined to retroperitoneal nodes below the diaphragm

Stage 3: Metastases outside the retroperitoneal nodes or above the diaphragm
111. Germ cell tumors often secrete what hormones or enzymes?
AFT, HCG, placental ALPHOS, placental lactogen, and LDH.

HCG, AFP, and LDH are widely used and have proved to be valuable in the Dx and management of testicular CA.
112. What molecular markers may be of use in the Dx of germ cell tumors?
The transcription factor encoded by OCT3/4 gene is expressed in primordial germ cells, as well as in seminomas and embryonal CAs, and testicular germ cell tumors reveal inactivation of the X-chromosome. These can be detected by immunoperoxidase and PCR techniques, respectively.
113. What is the importance of LDH?
LDH is produce din many tissues, including skeletal and cardiac muscles; hence, elevations of this enzymes are not specific for testicular tumors.

The degree of LDH elevation correlates with the mass of tumor cells, however, and the levels of this enzyme provide a tool to assess tumor burden.
114. Importance of AFP?
AFP is the major serum protein of the early fetus and is synthesized by the fetal gut, liver cells, and yolk sac. One year after birth, the serum levels of AFP fall to less than 16 ng/mL, which is undetectable in most assay.

Marked elevation of AFP is produced by yolk sac tumors.
115. Importance of HCG?
HCG is a glycoprotein containing 2 dissimilar polypeptide unites called α and β. It is normally synthesized and secreted by the placental syncytiotrophoblast.

The β subunit of HCG has unique sequences that are not shared with other hormones; therefore, the detection of HCG in the serum is based on a radioimmunoassay using antibodies to its β chain.

Elevated levels of HCG is produced by choriocarcinoma elements.
116. What are the 4 reasons for why the values of these markers are important?
1. In the evaluation of testicular masses.
2. In the staging of testicular germ cell tumors. For ex, after orchiectomy, persistent elevation of HCG or AFP indicates stage II disease even if lymph nodes appear of normal size by CT.
3. In assessing tumor burden. The levels of LDH in particular are related to tumor mass and provide an independent prognostic marker in pts with these tumors.
4. In monitoring the response to therapy. After eradication of tumors, there is a rapid fall in serum level of AFP and HCG.
117. What are the clinical features of mixed germ cell tumors?
The therapy and prognosis depend on the clinical stage and histologic type. Seminoma, which is radiosensitvie and tends to remain localized, has the best pronosis. More than 95% of pts with stage 1 and 2 disease can be cured.

Among NSGCT's the histologic subtype doesn't matter. Although they don't share the excellent prognosis of seminoma, approx 90% of pts can achieve complete remission w/aggressive chemo, and most can be cured.

W/all testicular tumors, distant metastases, if present, usually occur w/in the first 2 years after Tx.
118. What are Leydig (interstitial) cell tumors?
Tumors of Leydig cells are particularly interesting b/c they may elaborate androgens or combinations of androgens and estrogens, and some have also elaborated corticosteroids.

They arise at any age, although msot of the reported cases have been noted between 20-60.

As with other testicular tumors, the most common presenting feature is testicular swelling, but in some pts, gynecomastia may be the first symptom. In children, hormonal effects, manifested primarily as sexual precocity, are the dominating features.

Approx 10% of the tumors in adults are invasive and produce metastases; most are benign.
119. What is the morphology of Leydig cell tumors?
These neoplasms form circumscribed nodule, usually less than 5 cm in diameter. They have a distinctive golden brown, homogeneous cut surface.

Histologically, the Leydig cells are large and round or polygonal, and they have an abundant granular eosinophilic cytoplasm with a round central nucleus. Cell boundaries are often indistinct.

***The cytoplasm freq contains lipid granules, vacuoles, or lipofuscin pigment, but most characteristically, rod-shaped crystalloids of Reinke occur in about 25% of tumors.***
120. What are Sertoli cell tumors (androblastomas)?
Sertoli cell tumors may be composed entirely of Sertoli cells or may have a component of granulosa cells. Some induce endrocrinologic changes. Either estrogens or androgens may be elaborated but only infrequently in sufficient quantity to cause precocious masculinization or feminization.

Occasionally, as with Leydig cell tumors, gynecomastia appears.
121. What is the morphology of Sertoli cell tumors?
These neoplasms appear as firm, small nodules with a homogeneous gray-white to yellow cut surface.

Histologically, the tumor cells are arranged in distinctive trabeculae w/a tendency to form cordlike structures resembling immature seminiferous tubules.

Most Sertoli cell tumors are benign, but occasional tumors (approx 10%) are more anaplastic and pursue a malignant course.
122. What is a gonadoblastoma?
Gonadoblastomas are rare neoplasms containing a mixture of germ cells and gonadal stromal elements, almost always arising in dysgenetic gonads.

In some cases, the germ cell component becomes malignant, giving rise to an invasive seminoma.
123. What is testicular lymphoma?
Although not primarily a tumor of the testis, testicular lymphoma can present with only a testicular mass.

***Lymphomas account for 5% of testicular neoplasms and constitute the most common form of testicular neoplasm in men over the age of 60.***

In most cases, disseminated disease is already present at the time of detection of the testicular mass; only rarely does it remain confined to the testis.
124. What is the histologic type of lymphoma in almost all testicular lymphomas?
The histologic type in almost all cases is the diffuse large cell lymphoma (DLCBL).

The prognosis is extremely poor.
125. When do chyloceles present?
Chyloceles are almost always found in pts with elephantiasis who have widespread, severe lymphatic obstruction.
126. Where are the three points of narrowing in the ureters?
1. At the ureteropelvic junction
2. Where they enter the bladder
3. Where they cross the iliac vessels

*These all provide loci where renal calculi may become impacted when they pass from the kidney to the bladder.
127. What are the congenital anomalies of the ureters?
1. Double ureters
2. Uteropelvic junction obstruction
3. Diverticula
4. Hydroureter
5. Megaloureter
128. What are double ureters?
Double ureters (derived from a double or split ureteral bud) are almost invariably associated w/either totally distinct double renal pelves or with anomalous development of a large kidney having a partially bifid pelvis terminating in separate ureters.

Double ureters may pursue separate courses to the bladder but commonly are joined w/in the bladder wall and drain thru a single ureteral orifice. The majority of double ureters are unilateral and of no clinical significance.
129. What is the most common cause of hydronephrosis in infants and children?
Ureteropelvic junction obstruction. It usually presents in infants or children, much more commonly in boys, usually in the left ureter. However, it is bilateral in 20% of cases and may be associated with other congenital anomalies.

In adults, ureteropelvic junction obstruction is more common in women and is most often unilateral.

*There is agenesis of the kidney on the opposite side in a significant number of cases, probably resulting from obstructive lesions in utero.
130. What are diverticula of the ureters?
Diverticula, saccular outpouchings of the ureteral wall, are uncommon lesions that are usually asymptomatic and found incidentally.

They appear as congenital or acquired defects and are of importance as pockets of stasis and secondary infections.
131. What is a hydroureter?

What is a megaloureter?
Dilation (hydroureter), elongation, and tortuosity of the ureters may occur as congenital anomalies or as acquired defects. Congenital hydroureter is thought to reflect some neurogenic defect in the innervation of the ureteral musculature.

Massive enlargement of the ureter is known as megaloureter and is probably due to a function defect of ureteral muscle. Hydronephrosis and decreased renal function results if the lesion goes untreated.
132. What is ureteritis?
Ureteritis may develop as one compponeent of UTIs. The morphologic changes are entirely nonspecific. Only infrequently does such ureteritis make a significant contribution to the clinical problem.

Persistence of infection or repeated acute exacerbations may give rise to chronic inflammatory changes w/in the ureters.
133. What is the morphology of ureteritis?

(What is ureteritis follicularis?)
In certain cases of long-standing chronic ureteritis, specialized reaction patterns are sometimes observed.

The accumulation or aggregation of lymphocytes in the subepithelial region may cause slight elevations of the mucosa and produce a fine granular mucosal surface (ureteritis follicularis).
134. What is the morphology of ureteritis?

(What is ureteritis cystica?)
At other times, the mucosa may become sprinkled w/fine cysts varying in diameter from 1-5 mm *ureteritis cystica). The cysts may aggregate to form small, grapelike clusters.

Histologic sections thru such cysts demonstrate a lining of modified transitional epithelium w/some flattening of the superficial layers of cells.
135. What are the two most common neoplasias of the ureters?
Fibroepithelial polyps and leiomyomas.

The fibroepithelial polyp is a tumor-like lesion that grossly presents as a small mass projecting into the lumen. The lesion occurs more commonly in the ureters (left more than the right) but may also appear in the bladder, renal pelves, and urethra. The polyp presents as a loose, vascularized connective tissue mass lying beneath the mucosa.
136. What about primary malignant tumors of the ureter?
Primary malignant tumors of the ureter follow patterns similar to those arising in the renal pelvis, calyces, and bladder, and the majority are transitional cell CAs.

They cause obstruction of the ureteral lumen and are found most frequently during the 6th and 7th decades of life.

They are sometimes multiple and occasionally occur concurrently w/similar neoplasms in the bladder or renal pelvis.
137. What are the 5 important intrinsic causes of ureteral obstruction?
1. Calculi
2. Strictures
3. Tumors
4. Blood clots
5. Neurogenic
138. What are the 4 extrinsic causes of ureteral obstruction?
1. Pregnancy
2. Periureteral inflammation
3. Endometriosis
4. Tumors
139. What is the main difference between proximal and distal causes of ureteral obstruction?
Unilateral obstruction results from proximal causes, whereas bilateral obstruction arises from distal causes, such as BPH.
140. What is sclerosing retroperitoneal fibrosis?
This refers to an uncommon cause of ureteral narrowing or obstruction characterized by a fibrous proliferative inflammatory process encasing the retroperitoneal structures and causing hydronephrosis.
141. What is the pathogenesis of sclerosing retroperitoneal fibrosis?

What is Ormond disease?
The disorder occurs in middle to late age. In some cases, specific causes can be identified such as drugs, adjacent inflammatory conditions, or malignant disease.

*However, 70% of cases have no obvious cause and are considered primary or idiopathic (Ormond disease)
142. What are the microscopic features of sclerosing retroperitoneal fibrosis?
On microscopic exam, the inflammatory fibrosis is marked by a prominent inflammatory infiltrate of lymphocytes, often with germinal centers, plasma cells, and eosinophils.

Sometimes, foci of fat necrosis and granulomatous inflammation are seen in and about the fibrosis.
143. What are the congenital anomalies of the bladder?
1. Diverticula
2. Exstrophy
3. Miscellaneous anomalies (vesicoureteral reflux, congenital fistulas, persistent urachus, urachal cysts)
144. What are bladder diverticula?
A bladder or vesical diverticulum consists of a pouchlike eversion or evagination of the bladder wall. Diverticula may arise as congenital defects but more commonly are acquired lesions frmo persistent urethral obstruction.

Although most diverticula are small and asymptomatic, they may be clinically significant, as they constitute sites urinary stasis and predispose to infection and the formation of bladder calculi. They may also predispose to vesicoureteral reflex.
145. What cause congenital vs. acquired diverticula?
Congenital diverticula may be due to a focal failure of development of the normal musculature or to some urinary tract obstruction during fetal development.

Acquired diverticula are most often seen w/prostatic enlargement (BPH or neoplasia), producing obstruction to urine outflow and marked muscle thickening of the bladder wall.

In both the congenital and acquired forms, the diverticulum usually consists of a round to ovoid, saclike pouch the varies from less than 1 cm to 5 to 10 cm in diameter.
146. What is exstrophy of the bladder?
Exstrophy of the bladder implies the presence of a developmental failure in the anterior wall of the abdomen and in the bladder, so that the bladder either communicates directly thru a large defect with the surface of the body or lies as an open sac.

These lesions are amenable to surgical correction, and long term survival is possible. ***There is an increased tendency toward the development of CA later in life, mostly adenocarcinoma of the colon.
147. What is a persistent urachus?
Rarely, the urachus may remain patent in part or in whole (persistent urachus). When it is totally patent, a fistulous urinary tract is created that connects the bladder with the umbilicus. At times, the umbilical end or the bladder end remains patent, while the central region is obliterated.

This may predispose to infections, urachal cysts, or carcinomas (mostly glandular tumors resembling colonic adenocarcinomas).
148. What are the common etiologic agents of cystitis?
1. E. coli
2. Proteus
3. Klebsiella
4. Enterobacter
5. Candida albicans
6. Schistosoma haematobium
7. Chlamydia
8. Mycoplasma
149. What is the morphology of cystitis?

What is the morphology of hemorrhagic cystitis?
Most cases of cystitis take the form of nonspecific acute or chronic inflammation of the bladder. In gross appearance, there is hyperemia of the mucosa, sometimes associated with exudate.

When there is a hemorrhagic component, the cystitis is designated hemorrhagic cystitis. This form of cystitis sometimes follows radiation injury or antitumor chemo and is often accompanied by epithelial atypia. *Adenovirus infection also causes a hemorrhagic cystitis
150. What is the morphology of suppurative cystitis and ulcerative cystitis?
The accumulation of large amts of suppurative exudate may merit the designation of suppurative cystitis.

When there is ulceration of large areas of the mucosa, or sometimes the entire bladder mucosa, this is known as ulcerative cystitis.
151. What is the morphology of chronic cystitis?
Persistence of infection leads to chronic cystitis, which differs from the acute form only in the character of the inflammatory infiltrate. There is more extreme heaping up of the epithelium w/the formation of red, friable, granular, sometimes ulcerated surface.

Chronicity of the infection gives rise to fibrous thickening in the muscularis propria and consequent thickening and inelasticity of the bladder wall.
152. What is the morphology of the follicular and eosinophilic variants of chronic cystitis?
Follicular cystitis is characterized by the aggregation of lymphocytes into lymphoid follicles w/in the bladder mucosa and underlying wall.

Eosinophilic cystitis is manifested by infiltration with submucosal eosinophils together with fibrosis and occasionally giant cells.
153. What is the triad of symptoms in clinical cystitis?
1. Frequency which in acute cases may necessitate urination every 15-20 min
2. Lower abdominal pain localized over the bladder region or in the suprapubic region
3. Dysuria

Associated w/these localized changes, there may be systemic signs of inflammation such as elevation of temp, chills, and general malaise.
154. What is interstitial cystitis?
This is a persistent, painful form of chronic cystitis occurring most freq in women and associated w/inflammation and fibrosis of all layers of the bladder wall.

It is characterized clinically by intermittent, often sever, suprapubic pain, urinary frequency, urgency, hematuria, and dysuria w/o evidence of bacterial infections, and cytoscopic findings such as fissures and punctate hemorrhages in the bladder mucosa after luminal distention.
155. What are Hunner ulcers?
Some but not all pts exhibit morphologic features of chronic mucosal ulcers (Hunner ulcers), which is termed the late (classic, ulcerative) phase.

Inflammation cells and granulation tissue may involve the mucosa, lamina propria, and muscularis, and mast cells may be particularly prominent.

In the early (nonclassic, nonulcerative) form, recent submucosal hemorrhages are noted.
156. What is malacoplakia?
This designation refers to a peculiar pattern of vesical inflammatory reaction characterized macroscopically by soft, yellow, slightly raised mucosal plaques 3-4 cm in diameter and histologically by infiltration with large, foamy macrophages with occasional multinucleate giant cells and interspersed lymphocytes.

The macrophages have abundant granular cytoplasm. The granularity is PAS positive.

*In addition, laminated mineralized concretions resulting from depositions of calcium in enlarge lysosomes, known as Micaelis-Gutmann bodies are typically present in the macrophages and between cells.
157. What causes malacoplakia?
It is clearly related to chronic bacterial infection, mostly by E.coli or occasionally Proteus species.

It occurs with increased freq in immunosuppressed transplant recipients.

The unusual-appearing macrophages and giant phagosomes point to defects in phagocytic or degradative function of macrophages such that phagosomes become overloaded w/undigested bacterial products.
158. What is polypoid cystitis?
Polypoid cystitis is an inflammatory condition resulting from irritation to the bladder mucosa.

Although indwelling catheters are the most commonly cited culprits, any injurious agent may give rise to this lesion.

*The urothelium is thrown into broad, bulbous, polypoid projections as a result of marked submucosal edema.

This type of cystitis may be confused w/papillary urothelial CA both clinically and histologically.
159. What is cystitis glandularis and cystitis cystica?
These terms refer to common lesions of the urinary bladder in which nests of transitional epithelium grow downward into the lamina propria and undergo transformation of their central epithelial cells into cuboidal or columnar epithelium lining (cystitis glandularis) or cystic spaces lined by urothelium (cystitis cystica).

*In a variant of cystitis glandularis, goblet cells are present, and the epithelium resembles intestinal mucosa (intestinal or colonic metaplasia)
160. What is the morphology of cystitis cystica?
In cystitis cystica, the cysts are usually 0.1 to 1 cm in diameter, filled with clear fluid, and lined by cuboidal or urothelial cells.
161. When does squamous metaplasia occur?
As a response to injury, the urothelium often converts to squamous epithelium, which is a more durable lining.

This contrasts with the normal finding of glycogenated squamous epithelium commonly found in women at the trigone.
162. What is nephrogenic metaplasia (nephrogenic adenoma)?
Nephrogenic metaplasia also represents a reaction of the urothelium to injury. The overlying urothelium may be focally replaced by cuboidal epithelium, which can assume a papilllary growth pattern.

In addition a tubular proliferation in the underlying lamina propria and superficial detrusor muscle may produce lesions that histologically mimic a CA.
163. What are urothelial (transitional cell) tumors?
These tumors represent about 95% of all bladder tumors and run the gamut from small benign lesions that may never recur, to tumors of low or indeterminate malignant potential, to lesions that invade the bladder wall and frequently metastasize. Many are multifocal at presentation.

Although most commonly seen in the bladder, any of the urothelial lesions described here may be seen at any site where there is urothelium, from the renal pelvis to the distal urethra.
164. What are the two distinct precursor lesions to invasive urothelial CA?
1. The more common are noninvasive papillary tumors
2. Flat urothelial CA (CIS)
165. What are noninvasive papillary tumors?

What are CIS lesions?
These lesions demonstrate a range of atypia, and several grading systems exist to reflect their biologic behavior.

The CIS lesion is by definition high grade and hence not assigned a grade. In about 1/2 the pts w/invasive bladder CA, at the time of presentation the tumor has already invaded the bladder wall, and there is no associated precursor lesion.
166. What sign indicates a major decrease in survival in invasive urothelial CA?
Although invasion into the lamina propria worsens the prognosis, the major decrease in survivial is associated w/tumor invading the muscularis propria (detrusor muscle)

Once muscularis propria invasion occurs, there is a 50% 5 year mortality rate.
167. What are the morphological patterns of urothelial cell tumors?
They may vary from purely papillary to nodular or flat. The tumors may be invasive or noninvasive.

Papillary lesions appear as red, elevated excresences varying in size from less than 1 cm in diameter to large masses up to 5 cm in diameter.

Multicentric origins may produce separate tumors. The histologic changes encompass a spectrum from benign papilloma to highly aggressive anaplastic CAs.

Overall, the majority of papillary tumors are low grade. Most arise from the lateral or posterior walls at the bladder base.
168. What is the morphology of (exophytic) papillomas in the bladder?
Papillomas represent 1% or fewer of bladder tumors, commonly seen in young pts.

The tumors usually arise singly as small (0.5 to 2.0 cm), delicate structures, superficially attached to the mucosa by a stalk.

The individual finger-like papillae have a central core of loose fibrovascular tissue covered by transitional epithelial cells ***that are histologically identical to normal urothelium.***
169. What is the morphology of inverted papillomas?
In contrast to the above exophytic papilloma, inverted papillomas are benign lesions consisting of interanastomosing cords of cytologically bland urothelium extending down into the lamina propria.
170. What are papillary urothelial neoplasms of low malignant potential (PUNLMP)?
PUNLMP share many histologic features with papillomas, the only differences being either thicker urothelium or diffuse nuclear enlargement in PUNLMP. Mitotic figures are rare.

At cytoscopy, PUNLMP tend to be larger than papillomas and may be indistinguishable from low and high grade papillary CAs.
171. What are low-grade papillary urothelial CAs?
Low-grade papillary urothelial CAs are characterized by an orderly appearance both architecturally and cytologically.

The cells are evenly spaced and cohesive. There is minimal but definite evidence of nuclear atypia consisting of scattered hyperchromatic nuclei, infrequent mitotic figures predominantly towards the base, and mild variation in nuclear size and shape.

Only rarely do these tumors pose a threat to the pt's life.
172. What are high-grade papillary urothelial CAs?
High-grade papillary urothelial CAs contain cells that may be dyscohesive and have large hyperchromatic nuclei. Some of the cells show frank anaplasia.

Mitotic figures, including atypical ones, are frequent.

Architecturally, there is disarray with loss of polarity. These tumors have a much higher incidence of invasion into the muscular layer, a higher risk of progression than low-grade lesions, and significant metastatic potential.
173. Where do aggressive invasive bladder tumors typically invade?
Aggressive tumors may not only extend into the bladder wall, but with progression, invade the adjacent prostate, seminal vesicles, ureters, and retroperitoneum.

Some produce fistulous communications to the vagina or rectum. About 40% of these deeply invasive tumors metastasize to regional lymph nodes.

Hematogeneous dissemination, principally to the liver, lungs, and bone marrow, generally occurs late and only with highly anaplastic tumors.
174. What defines CIS?

How is it similar to a high-grade papillary urothelial CA?
*Carcinoma in situ is defined by the presence of any cytologically malignant cells w/in a flat urothelium.

CIS may range from full-thickness cytologic atypia to scattered malignant cells in an otherwise normal urothelium.

A common feature shared with high-grade papillary urothelial CA is the lack of cohesiveness, which leads to shedding of malignant cells into the urine.
175. What is the morphology of CIS?
Grossly, CIS usually appears as an area of mucosal reddening, granularity, or thickening w/o an intraluminal mass.

It is commonly multifocal and may involve most of the bladder surface and extend into the ureters and urethra.

If untreated, 50-75% of CIS cases progress to muscle-invasive CA.
176. What are the clinical features of invasive urothelial CA?
Invasive urothelial CA, which is detected early, may be superficial in the lamina propria and can be associated w/either papillary urothelial CA, usually high grade, or with CIS.

**The most important factor in determining prognosis is the extent of spread, or staging.
177. What are the unusual variants of urothelial CA?
These include the nested variant w/deceptively bland cytology lymphoepithelioma-like CA and small cell CA.
178. What are squamous cell CAs of the bladder?
These represent about 3-7% of bladder CAs in the US, but in countries endemic for urinary schistosomiasis, they occur much more frequently.

Pure squamous cell CAs are nearly always associated with chronic bladder irritation and infection.
179. What are mixed urothelial cell CAs with areas of squamous CA?
These are more frequent than pure squamous cell CAs.

Most are invasive, fungating tumors or infiltrative and ulcerative. True papillary patterns are almost never seen.

*The differentiation varies widely, from the highly differentiated lesions producing abundant keratohyaline pearls to anaplastic giant cell tumors showing little evidence of squamous differentiation

They often cover large areas of the bladder and are deeply invasive by the time of discovery.
180. What are adenocarcinomas of the bladder?
Adenocarcinomas of the bladder are rare and they are histologically identical to adenocarcinomas seen in the GI tract.

Some arise from urachal remnants or in association with extensive intestinal metaplasia.

Rare variants include the highly malignant signet-ring cell CA, and mixed adenocarcinoma and urothelial cell CAs.
181. Where do urachal adenocarcinomas usually occur in the bladder?
Urachal tumors occur in the dome or anterior wall, arise within the wall rather than from the mucosa, and extend out of the bladder toward the umbilicus.
182. What is the prevalence of bladder CA?
Resembles that of bronchogenic CA, being more common in men than in women, in industrialized nations than in developing nations, and in urban than in rural dweller.

About 80% of pts are between the ages of 50-80. It is not familial.
183. What are the 6 big risk factors for urothelial CA?
1. Cigarette smoking*
2. Industrial exposure to arylamines, particularly 2-naphthylamine
3. Schistosoma haematobium
4. Heavy long term exposure to cyclophosphamide
5. Long term use of analgesics
6. Prior exposure of the bladder to radiation
184. What mutations are linked to superficial papillary tumors and occasionally noninvasive flat tumors?
Chromosome 9 deletions.

Chromosome 9 (9p, 9q) deletions are the only genetic changes that are present frequently in superficial papillary tumors and occasionally noninvasive flat tumors.
185. What is the result of 9p deletion?
The 9p deletions (9p21) involve the tumor-suppressor gene p16INK4a, which encodes an inhibitor of a cyclin-dependent kinase.
186. What mutations are linked to invasive urothelial cell CAs?
Deletions of 17p, including the region of the p53 gene, as well as mutations in the p53 gene.
187. What are the two pathways for bladder carcinogenesis based on these genetic mutations?
1. Initiation by deletions of tumor-suppressor genes on 9p and 9q, leading to superficial papillary tumors, a few of which may then acquire p 53 mutations and progress to invasion

2. Initiation by p53 mutations, leads to CIS, and with loss of chromosome 9, progresses to invasion.
188. What are the clinical features of bladder tumors?
Bladder tumors produce painless hematuria, sometimes w/frequency and urgency. About 60% of neoplasms, when first discovered, are single, and 70% are localized to the bladder.

Patients with urothelial tumors, whatever their grade, have a tendency to develop new tumors after excision, and recurrences may exhibit a higher grade.
189. What are benign mesenchymal tumors?
A great variety of benign mesenchymal tumors may arise in the bladder. Collectively, they are rare. The most common is leiomyoma. They all tend to grow as isolated, intramural, encapsulated, oval to spherical masses, varyign in diameter up to several centimeters. On occasion, they assume submucsal pedenculated positions.

They have the histologic features of their counterparts elsewhere.
190. What are sarcomas in the bladder?

What are the most common ones in children? Adults?
These are are. Inflammatory pseudotumors, postoperative spindle cell nodules, and various carcinomas may assume sarcomatoid growth patterns, and be mistaken histologically for sarcomas.

*The most common sarcoma in infancy or childhood is embryonal rhabdomyosarcoma. The most common sarcoma in the bladder in adults is leiomyosarcoma.
191. What is the morphology of sarcomas?
As a group, sarcomas tend to produce large masses that protrude into the vesicle lumen. Their soft, fleshy, gray-white gross appearance suggests their sarcomatous nature.
192. What is the morphology of bladder obstruction?
In the early stages, there is only some thickening of the bladder wall, presumably due to hypertrophy of the smooth muscle.

The mucosal surface at this time may be entirely normal. W/progressive hypertrophy of the muscle coat, the individual muscle bundles greatly enlarge and produce trabeculation of the bladder wall. In the course of time, crypts form and may then become converted into true acquired diverticula.
193. What is a urethral caruncle?
A urethral caruncle is an inflammatory lesion presenting as a small, red, painful mass about the external urtheral meatus in the female pt.

The lesion consists of a hemispheric, friable, 1-2 cm nodule that occurs singly, either just outside or just inside the external urethral meatus.

***On histologic exam, it is composed of a highly vascularized, young, fribroblastic connective tissue, usually heavy infiltrated with leukocytes.
194. In which regions of the prostate do cancers arise?

Most hyperplasias arise in the transitional zone, whereas most carcinomas originate in the peripheral zone.
195. What are the three important pathologic processes that affect the prostate gland?
1. Inflammation
2. Benign nodular enlargement
3. Tumors

Of these three, the benign nodular enlargements are by far the most common and occur so often in advanced age that they can almost be considered as normal in the aging process.
196. What are the different categories of prostatitis?
1. Acute and chronic bacterial prostatitis
2. Chronic abacterial prostatitis
3. Granulomatous prostatitis
197. What is acute bacterial prostatitis?
Acute bacterial prostatitis typically results from bacteria that cause UTIs. Thus, most cases are caused by various strains of E. coli, other gram-negative rods, enterococci, and stapylocci.

Prostatitis sometimes follows some surgical manipulation on the urethra or prostate gland.

Clinically, acute bacterial prostatitis is associated w/fever, chills, and dysuria. On rectal exam, the prostate is tender and boggy.
198. What is chronic bacterial prostatitis?
A common clinical setting is recurrent UTIs caused by the same organism. It may present w/low back pain, dysuria, and perineal and suprapubic discomfort.

B/c most antibiotics penetrate the prostate poorly, bacteria find a safe haven in the parenchyma and constantly see the urinary tract.
199. What is chronic abacterial prostatitis?
Chronic abacterial prostatitis is the most common form of prostatitis seen today.

Clinically, it is indistinguishable from chronic bacterial prostatitis. There is no history, however, of recurrent UTI.

Expressed prostatic secretions contain more than 10 leukocytes per high power field, but bacterial cultures are uniformly negative.
200. What is granulomatous prostatitis?
In the US, the most common cause is related to instiallation w/in the bladder of Bacillus Calmette-Guerin (BCG) for treatment of superficial bladder cancer.

BCG is an attenuated tubercuous strain that gives rise to a histologic picture in the prostate indistinguishable from that seen w/systemic tuberculosis.

Fungal granulomatous prostatitis is typically seen only in immunocompromised hosts.
201. What is the morphology of acute prostatitis?
Acute prostatitis may appear as minute, disseminated abscesses; as large, coalescent focal areas of necrosis; or as a diffuse edema, congestion, and boggy suppuration of the entire gland. When diffuse, they cause an overall soft, spongy enlargement of the gland.

*Biopsy of the prostate in a patient w/acute prostatitis is contraindicated as it may lead to sepsis.
202. What is the morphology of chronic prostatitis?
This Dx should be restricted to those cases of inflammatory reaction int eh prostate characterized by the aggregation of numerous lymphocytes, plasma cells, and macrophages as well as neutrophils w/in the prostatic substance only if accompanied by clinical signs and symptoms of chronic prostatitis.
203. What is nodular hyperplasia (BPH)?
BPH is an extremely common disorder in men over 50. It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting int he formation fo large, failurly discrete nodules in teh periurethral region of the prostate. When sufficiently large, the nodules compress and narrow the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra.
204.What is the pathogenesis of BPH?
Androgens are the cause, baby... DHT, a metabolite of testosterone, is the ultimate mediator of prostatic growth. It binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. While DHT appears to be the major factor, estrogens also appear to play a role, perhaps by rendering cells more susceptible to the action fo DHT.

In addition, clinical symptoms of lower urinary tract obstruction are also due to smooth muscle mediated contraction of the prostate. The tension of prostate smooth muscle is mediated by the α1-adrenoreceptor localized to the prostatic stroma.
205. What is the morphology of BPH?

In the usual case, the prostate weighs between 60-100 gm.

BPH originates almost exclusively in the inner aspect of the prostate gland, in the transition zone.

The first nodules are composed almost entirely of stromal cells; later, predominantly epithelial nodules arise.

In some cases, nodular enlargement may project up into the floor of the urethra as a hemispheric mass directly beneath the mucosa of the urethra, which is termed "median lobe hypertrophy" by clinicians.
206. What is the morphology of BPH?

On cross section, the nodules usually are fairly readily identified. They vary in color and consistency. In nodules w/primarily glandular proliferation, the tissue is yellow-pink w/a soft consistency, and a milky white prostatic fluid oozes out of these areas.

In those primarily due to fibromuscular involvement, each nodule is pale gray, tough, does not exude fluid, and is less clearly demarcated from the surrounding prostatic capsule.
207. What is the morphology of BPH?

Microscopically, the hallmark of BPH is nodularity due to glandular proliferation or dilation and to fibrous or muscular proliferation of the stroma.

The Dx of BPH cannot usually be made via needle biopsy, as the histology of glandular or mixed glandular-stroma nodules of BPH cannot be appreciated on this limited sampling. Also, needle biopsies do not usually sample the transition zone where BPH occurs.
208. What are two other histologic changes associated w/BPH?
1. Foci of squamous metaplasia
2. Small areas of infarction

The former tends to occur in the margins of the foci of infarction as nests of metaplastic reactive squamous cells that can be confused with adenocarcinoma of the prostate or urothelial CA involving the prostate.
209. What is the clinical course of BPH?
Symptoms are related to two secondary effects: (1) compression of the urethra w/difficulty in urination and (2) retention of urine in teh bladder w/subsequent distention and hypertrophy of the bladder, infection fo the urine,a nd development of cystitis and renal infections.

Pts experience frequency, nocturia, difficulty starting and stopping, overflow dribbling, and dysuria. Also, the pts are unable to empty the bladder completely.

However, nodular hyperplasia is not considered to be a premalignant lesion.
210. What is adenocarcinoma of the prostate?

In which populations is it most common?
Adenocarcinoma of the prostate is the most common form of cancer in men and is the second leading cause of cancer death.

It is typically a disease of men over age 50. It is rare among Asians; whereas it common among US white populations. Thus, the initial molecular events that give rise to latent cancers occur at the same rate in Asian and American men, the probability of acquiring additional mutations, presumably environmentally induced, is lower in Asian men.
211. What is the pathogenesis of adenocarcinoma of the prostate?
Androgens also play a role. Neoplastic epithelial cells, similar to their normal counterparts, possess androgen receptors.

Androgen receptor gene amplification may also influence androgen sensitivity of prostatic epithelium. The AR gene is polymorphic, w/individuals having variable lengths of CAG repeats. Studies have shown that prostate cells w/short CAG repeats have an increased sensitivity to androgens. The shortest CAG repeats on average are found in African Americans, Caucasians have an intermediate length, and Asians have the longest.
212. Is there a hereditary form of prostate cancer?
In approx 10% of white American men, the development of prostate CA has been linked to germ line inheritance of prostate cancer susceptibility genes.

In 1/3 of these familial cases, a susceptibility gene has been mapped to chromosome 1q24-25.

Men with relatives w/prostate CA are at greater risk and those with a strong family history of prostate CA also tend to develop the disease at an earlier age.
213. What genetic events take place in early events in prostate carcinogenesis?

Late events?
Putative cancer suppressor genes that are lost early in prostate carcinogenesis have been localized to chromosomes 8p, 10q, 13q, and 16q.

p53 mutations are late events in prostate carcinogenesis.

Other tumor suppressor genes that are though to play a role in prostate CA are PTEN and KAI1.

Prostate CAs also show a relatively freq loss of E-cadherin and CD44.
214. What is one of the most common genetic alterations in prostate CA?
Hypermethylation of glutathione S-transferase (GSTP1) gene promoter.

More than 90% of prostate CAs show hypermethylation of the gene, which turns off its expression. The GSTP1 gene is an important part of the pathway that prevents damage from a wide range of carcinogens.
215. What is the morphology of prostate adenocarcinomas?
Prostate CA refers to the common or acinar variant of prostate CA.

In approx 70% of cases, the CA arises in the peripheral zone of the gland, classically in a posterior location, often rendering it palpable on rectal exam.

Characteristically, on cross section, the neoplastic tissue is gritty and firm, but when embedded w/in the prostatic substance, it may be extremely difficult to visualize and be more readily apparent on palpation.
216. Metastatic spread of prostate CA goes to where...?
Local extension most commonly involves the seminal vesicles and the base of the urinary bladder.

Hematogenous spread occurs chiefly to the bones, particular to the axial skeleton. The bony metastases are typically osteoblastic. The bones that are most commonly involved are lumbar spine, proximal femur, pelvis, thoracic spine, and ribs.
217. What are the histologic characteristics of prostate CA?
Histologically, most lesions are adenocarcinomas that produce well-defined, readily demonstrable gland patterns. The neoplastic glands are typically smaller than benign glands and are lined by single layer of cuboidal or low columnar epithelium.

In contrast to benign glands, prostate CA glands are more crowded, characteristically lacking branching and papillary infolding.

*Benign glands contain basal cells that are absent in cancer.
218. What are high-grade prostatic intraepithelial neoplasias (PIN)s?
In approx 80% of cases, prostatic tissue removed for CA also harbors presumptive precursor lesions, referred to as high-grade PINs. These lesions consist of benign glands w/intra-acinar proliferation of cells that demonstrate nuclear anaplasia.

High-grade PIN consists of more widely separated, larger branching glands w/papillary infolding, in contrast to invasive CA, which is typically characterized by small, crowded glands w/straight luminal borders. PIN glands are surrounded by a patchy layer of basal cells an an intact basement membrane?
219. What are four lines of evidence that suggest high-grade PINs lead to prostate CA?
1. Both high-grade PIN and CA typically predominate in the peripheral zone.
2. Prostates containing CA have a higher freq and greater extent of high-grade PIN
3. High-grade PIN is also often seen in proximity to CA
4. Studies have found that many of the molecular changes that are seen in invasive CAs are also present in PIN
220. What is the grading and staging system of prostate CA?
The Gleason system stratifies prostate CAs into five patterns on the basis of glandular patterns.

Pattern 1 represents the most well differentiated tumors; by contrast, Pattern 5 tumors show no glandular differentiation and the tumor cells infiltrate the stroma.

Most tumors contain more than one pattern; the pathologist assigns a dominant pattern and then the second most prevalent pattern. The primary and secondary patterns are added to obtain a combined Gleason score. Tumors w/only one pattern are treated as if their primary and secondary patterns are the same, hence, the number is doubled.

Thus, 2-4 represent well differentiated; 5-6 intermediate-grade CA; 7 moderate to poorly differentiated CA; and 8-10 high grade CA.
221. What is the staging of prostatic CA?
Stage T1 refers to CA found incidentally either on TURP done for BPH (T1a and T1b depending on the extent and grade) or on needle biopsy typically performed for elevated PSA levels (stage T1c).

Stage T2 is organ confined CA

Stage T3a and T3b tumors show extraprostatic extension, w/and w/o seminal vesicle invasion, respectively.

Stage T4 reflects direct invasion of contiguous organs.

Spread of tumors to the lymph nodes is designated N1.
222. What are the symptoms of prostate CA?
Patients w/clinically advanced prostate CA may present w/urinary symptoms. Some pts come to attention b/c of back pain caused by vertebral metastases.

***The finding of osteoblastic metastases in bone is virtually diagnostic of prostate CA in men. The outlook for these patients is universally fatal.
223. How is prostate CA diagnosed and confirmed?
DREs may detect some early prostatic CA b/c of their posterior location, although the test suffers from both low sensitivity and specificity.

A transrectal biopsy is required to confirm the Dx. B/c microscopic metastases are usually missed by radiologic studies, most centers use pelvic lymphadenectomy as a staging procedure.
224. How is prostate CA treated?
The treatment and prognosis depends on the stage of the disease. Localized (T1 or T2) disease is treated primarily w/surgery or radiotherapy w/a 15 year survival rate of 90%.

Hormonal treatment can also be used (orchiectomy via synthetic analogues of LH) to treat advanced disease or combined w/radiotherapy for local disease.
225. What is PSA?
Prostate-specific antigen (PSA) is used in the Dx and management of prostate CA. PSA is a product of prostatic epithelium and is normally secreted in the semen.

Serum levels of PSA are elevated to a lesser extent in BPH than prostate CA, although there is a considerable overlap with 4 ng/mL being the cutoff point btwn normal and abnormal.
226. What five refinements in the estimation and interpretation of PSA values have been proposed?
1. PSA is organ-specific, yet not cancer-specific (other events can elevate PSA levels, i.e. infarcts, prostatitis, BPH, etc...)
2. PSA density factors out the contribution of benign prostatic tissue to serum PSA levels. This results in PSA levels produced per gram of prostate tissue.
3. Age specific PSA upper reference ranges are based on correspondingly higher PSA levels in older men.
4. PSA velocity (Rate of change of PSA) reflects the finding that men w/prostate CA demonstrate an increased rate of rise in PSA.
5. Percentage of free PSA measures the fraction of serum PSA bound to antichymotrypsin and a minor free fraction. Percentage of free PSA is lower in men w/prostate CA than in men w/BPH.
227.What is ductal adenocarcinoma of the prostate?
Ductal adenocarcinomas arising in peripheral ducts may present in a fashion similar to that of ordinary prostate CA, whereas those arising in the larger periurethral ducts present w/signs and symptoms similar to urothelial CA (hematuria and urinary obstructive symptoms).

Ductal adenocarcinomas are associated w/a relatively poor prognosis, although early detection and treatment may be curative w/surgery or radiation.
228. Prostate CAs that reveal abundant mucinous secretions are termed...?
Colloid carcinoma of the prostate.
229.What is the most aggressive variant of prostate CA?
Small cell CA. In some cases, the small cell CA represents de-differentiation of recurrent acinar adenocarcinoma; in other cases, men present w/de novo small cell CA of the prostate.

Almost all such cases are rapidly fatal.
230. What is the most common tumors to secondarily involve the prostate?
The most common tumor to secondarily involve the prostate is urothelial cancer.

Two distinct patterns of involvement exist. Large, invasive urothelial CAs can directly invade from the bladder into the prostate. Alternatively, carcinoma in situ of the bladder can extend into the prostatic urethra and down into the prostatic ducts and acini.
231. What are the names of the three class Ia antiarrhythmics?

What is their MOA?
1. Quinidine
2. Procainamide
3. Disopyramide

Class Ia antiarrhthmics produce a moderate block of voltage-gated sodium channels and block potassium channels in ventricular myocytes (decreases phase 0 upstroke velocity and prolongs repolarization) and SA nodal cells (shifts threshold to more positive potentials and decreases slope of phase 4 depolarization.

Quinidine also blocks ACh release from vagus nerve - vagolytic effect
232. Quinidine
PURPOSE: Conversion of atrial flutter or fibrillation and maintenance of normal sinus rhythm; paroxysmal supraventricular tachycardia; premature atrial or ventricular contractions; paroxysmal AV junctional rhythm or atach or vtach

ADVERSE: Torsades de pointes, complete AV block, vtach, agranulocytosis, thrombocytopenia, hepatotoxicity, acute asthma attack, respiratory arrest, angioedema, rare occurrence of systemic lupus; fatigue, headache, lightheadedness, widening of QRS complex and QT and PR intervals, hypotension, PVCs, tachycardia, diarrhea, cinchonism

CONTRA: History of torsades de pointes or prolonged QT interval; concurrent use of drugs that prolong QT interval; conduction defects
233. What are the 6 therapeutic considerations for quinidine?
1. Coadministration of other drugs known to prolong QT interval (such as thioridazine, ziprasidone) is contraindicated
2. Quinidine inhibits conversion of codeine to morphine, thereby reducing codeine's analgesic effect
3. Quinidine-induced digoxin toxicity occurs in a significant fraction of pts
4. Amiodarone, amprenavir, azole antifungals, cimetidine, and ritonavir increase quinidine levels
5. Coadministration of anticholinergics results in additive anticholinergic effects
6. An agents that slows AV nodal conduction (a beta blocker or calcium channel blocker) should be used in conjunction with quinidine to prevent an excessively rapid ventricular response in pts with atrial flutter.
234. What is the mechanism most likely responsible for quinidine-induced syncope?
Torsades de pointes
235. Procainamide
MOA: Moderate block of voltage-gated sodium channels and block potassium channels in ventricular myocytes (decreases phase 0 upstroke velocity and prolongs repolarization) and SA nodal cells (shifts threshold to more positive potentials and decreases slope of phase 4 depolarization.

PURPOSE: Sympatomatic PVCs, life-threatening vtach, maintenance of normal sinus rhythm after conversion of atrial flutter; malignant hyperthermia

ADVERSE: Same as quinidine, except fewer anticholinergic effects. Additionally, lupus-like syndrome may occur after prolonged use

CONTRA: Same as quinidine; also myasthenia gravis and SLE
236. Four therapeutic considerations for procainamide
1. Coadministration of drugs known to prolong QT interval is contraindicated
2. Procainamide does not alter plasma levels of digoxin
3. Ventricular rate may accelerate due to vagolytic effects on AV node; consider pretreatment with a cardiac glycoside
4. Baseline and periodic determination of ANA, and monitor for development of lupus-like sydnrome
237. How is procainamide processed in the liver?
Procainamide is acetylated in the liver to N-acetyl-procainamide (NAPA); this active metabolite produces the pure class III antiarrhythmic effects of prolonging the refractory period and lengthening the QT interval.

NAPA does not appear to cause the lupus-like side effects of procainamide.
238. Disopyramide
MOA: Moderate block of voltage-gated sodium channels and block potassium channels in ventricular myocytes (decreases phase 0 upstroke velocity and prolongs repolarization) and SA nodal cells (shifts threshold to more positive potentials and decreases slope of phase 4 depolarization.

PURPOSE: PVCs, vtach, conversion of atrial fibrillation, atrial flutter, and paroxysmal atrial trachycardia to normal sinus rhythm

ADVERSE: Same as quinidine, except more profound anticholinergic effects and fewer GI effects

CONTRA: Same as quinidine; additionally obstructive uropathy or glaucoma; conduction block between the atria and ventricles and sinus node dysfunction; *uncompensated heart failure**
239. What are four therapeutic considerations for disopyramide?
1. Coadministration of drugs known to prolong QT interval is contraindicated
2. Rifampin impairs antiarrhythmic activity to disopyramide
3. Ventricular rate may accelerate due to vagolytic effects on AV node; consider pretreatment with a cardiac glycoside
4. Disopyramide is commonly prescribed for patients who cannot tolerate quinidine or procainamide
240. What else can disopyramide be used for?
Disopyramide has the prominent but unexplained effect that it depresses cardiac contractility, which has led to its use in the treatment of hypertrophic obstructive cardiomyopathy and neurocardiogenic syncope.
241. What are the names of the class Ib antiarrhythmics?
1. Lidocaine
2. Mexiletine (oral analogue of lidocaine)
3. Phenytoin
242. How are class IB antiarrhythmics different than class IA?
In comparison to class IA antiarrhythmics which preferentially bind to open sodium channels, class IB drugs bind to both open and inactivated sodium channels.

Therefore, the more time sodium channels spend in the open or inactivated state, the more blockade the class IB drugs can effect.

Also, the major distinguishing characteristic of the class IB antiarrhythmics is their fast dissociation from sodium channels.

Thus, class Ib drugs exhibit use-dependent block in diseased myocardium, and have little effect on normal cardiac tissue.
243. Lidocaine & Mexiletine
MOA: Use-dependent block of voltage-gated Na⁺ channels in ventricular myocytes (decreases phase 0 upstroke velocity); may also shorten repolarization

PURPOSE: Ventricular arrhythmias in the context of MI, cardiac manipulation, or cardiac glycosides; status epilepticus; local anesthesia of skin or mucous membranes; pain, burning or itching; postherpetic neuralgia

ADVERSE: Seizures, asystole, bradycardia, cardiac arrest, new or worsened arrhythmias, respiratory depression, anaphylaxis, status asthmaticus, restlessness, stupor, tremor, hypotension, blurred or double vision, tinnitus

CONTRA: Stokes-Adams syndrome; Wolf-Parkinson White syndrome; severe SA, AV, or intraventricular block; decreased liver blood flow
244. What are 3 therapeutic considerations for lidocaine?
1. Dosage of both lidocaine and mexiletine should be adjusted when co-administered with P450 inhibitors (such as cimetidine) and inducers (such as barbiturates, phenytoin, or rifampin)
2. In severely ill patients, seizures may be the first sing of toxicity
3. Intramuscular injection of lidocaine can cause large increase in serum creatine kinase
245. What is mexiletine?
Analogue of lidocaine. While the efficacy of mexiletine is similar to that of quinidine, it does not prolong the QT interval and lacks vagolytic side effects.

The primary indication for mexiletine is life-threatening ventricular arrhythmia. In practice, however, it is often used as an adjunct to other antiarrhythmic agents.

For example, it is often used in combo with amiodarone in pts with ICDs and in pts with recurrent ventricular tachycardia.

Mexiletine is also used in combo with quinidine or sotalol to increase antiarrhythmic efficacy while reducing side effects.
246. Phenytoin
MOA: Use-dependent block of voltage-gated Na⁺ channels in ventricular myocytes (decreases phase 0 upstroke velocity); may also shorten repolarization

PURPOSE: Generalized tonic-clonic seizures, status epilepticus, non-epileptic seizures; seizures related to eclampsia, neuralgia, ventricular arrhythmias unresponsive to lidocaine or procainamide; arrhythmias induced by cardiac glycosides

ADVERSE: Agranulocytosis, leukopenia, pancytopenia, thrombocytopenia, hepatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis; ataxia, confusion, slurred speech, diplopia, nystagmus, gingival hyperplasia, nausea, vomiting, hirsutism

CONTRA: Hydantoin hypersensitivity; sinus bradycardia, SA node block, second or third degree AV block; Stokes-Adam syndrome
247.What is an important therapeutic consideration for phenytoin?
Phenytoin interacts with numerous drugs due to its hepatic metabolism. It is metabolized by P450 2C9/10 and P450 2C19. Other drugs that are metabolized by these enzymes can increase plasma concentration of phenytoin.

Phenytoin can also induce various P450s, such as P450 3A4, which can lead to increased metabolism of oral contraceptives and other drugs.
248. What are the names of the class IC antiarrhythmics?
1. Encainide
2. Flecainide
3. Moricizine
4. Propafenone

*These are the most potent Na⁺ channel blockers, and they have little or no effect on action potential duration. By markedly decreasing the rate of phase 0 upstroke of ventricular cells, these drugs suppress PVCs and paroxysmal supraventricular tachycardia.
249. Encainide, flecainide, morizicine, propafenone
MOA: Marked block of voltage-gated Na⁺ channels in ventricular myocytes (decreases phase 0 upstroke velocity)

PURPOSE: Sustained vtach, paroxysmal supraventricular tachycardia, paroxysmal atrial fibrillation unresponsive to other measures

ADVERSE: Cardiac arrest, heart failure, new or worsened arrhythmia, sinus-node dysfunction, marked decrease in conduction velocity, conduction block, dizziness, headache, syncope, visual disturbances, dyspnea

COTNRA: Cardiogenic shock, second or third-degree AV block, right BBB with left hemiblock, proarrhythmic effects in pts with atrial fibrillation or flutter
250. What are 4 therapeutic considerations for the class IC antiarrhythmics?
1. Associated with excessive mortality and non-fatal cardiac arrest; restrict use to pts who have failed other measures
2. Can worsen arrhythmia in pts with pre-existing ventricular tachyarrhythmias and in those with a history or myocardial infarction
3. May increase acute and chronic endocardial pacing threshold and suppress ventricular escape rhythms
4. Monitor levels in pts with significant hepatic impairment
251. What are the names of the class II antiarrhythmics?
1. Propanolol
2. Atenolol
3. Metoprolol
4. Acebutolol
5. Bisoprolol
6. Labetalol
6. Carvedilol
8. Pindolol
252. How do class II antiarrhythmics work?
These agents are β-adrenergic antagonists. They act by inhibiting sympathetic input to the pacing regions of the heart.

β₁-antagonists block the sympathetic stimulation of β₁-receptors in the SA and AV nodes. The AV node is more sensitive than the SA node to the effects of β₁-antagonists.
253. What are the two ways in which β₁-antagonists affect the action potentials of the SA and AV nodes?
1. Decreasing the rate of phase 4 depolarization. Decreasing the rate of phase 4 depolarization results in decreased automaticity, and this, in turn, reduces myocardial oxygen demand.

2. Prolonging repolarization. Prolonged repolarization at the AV node increase the effective refractory period, which decreases the incidence of re-entry
254. What are the β₁-antagonists typically used for?
β₁-antagonists are the most freq used agents in the treatment of supraventricular and ventricular arrhythmias precipitated by sympathetic stimulation.

β₁-antagonists have also been shown to reduce mortality after MI.
255. Propanolol
MOA: Propanolol, nadolol, and timolol interact with β₁ and β₂ receptors equally and do not block α receptors. These agents decrease slope of phase 4 depolarization and prolong repolarization.

PURPOSE: Tachyarhythmias caused by catecholamine stimulation. Hypertension, angina, heart failure, pheochromocytoma, glaucoma

ADVERSE: Bronchospasm, AV block, bradyarrhythmia, sedation, decreased libido, mask symptoms of hypoglycemia, depression, dyspnea, wheezing.

CONTRA: Bronchial asthma or COPD, cardiogenic shock, uncompensated cardiac failure, 2nd and 3rd degree AV block, severe sinus bradycardia

NOTES: Propanolol is extremely lipophilic, its concentration is sufficiently high that sedation and decreased libido may result.
256. Atenolol, metoprolol, acebutolol, and bisoprolol
MOA: β₁-selective adrenergic antagonists when administered in low doses. Metoprolol and atenolol have intermediate half lives (4-9 hrs). These agents decrease slope of phase 4 depolarization and prolong repolarization.

PURPOSE: These are second generation class II antiarrhythmics
257. Labetalol and carvedilol
MOA: Labetalol and carvedilol block α₁, β₁, and β₂ receptors (labetalol also acts as a weak partial agonist at β₂ receptors but has a 5-10x greater effect as a β blocker). These drugs decrease blood pressure by inducing vasodilation and antagonizing receptor mediated vasoconstriction. These agents decrease slope of phase 4 depolarization and prolong repolarization.

PURPOSE: Hypertension and angina (induce vasolitation)

ADVERSE: Same as propanolol, additionally, labetalol can cause hepatotoxicity - liver enzymes must be monitored
258. Pindolol
MOA: Pindolol is a partial agonist at β₁ and β₂ receptors. The drug blocks the action of endogenous norepinephrine at β₁ receptors and is useful in treating hypertension. These agents decrease slope of phase 4 depolarization and prolong repolarization.

As a partial agonist, pindolol also causes partial stimulation of β₁ receptors, leading to overall smaller decreases in resting heart rate and BP than those caused by pure β antagonists.

***Therefore, the drug may be preferable in hypertensive patients who have bradycardia or decreased cardiac reserve.
259. What are the 3 different adverse effects of beta blockers?
1. Antagonism at β₂-adrenergic receptors causes smooth muscle spasm, leading to bronchospasm, cold extremities and impotence. These effects are more commonly caused by the nonselective first generation β-antagonists.

2. Exaggeration of the therapeutic effects of β₁-receptor antagonism can lead to excessive negative inoptropic effects, heart block, and bradycardia.

3. Drug penetration into the CNS can produce insomnia and depression.
260. What are the names of the class III antiarrhythmic agents?
1. Ibutilide
2. Dofetilide
3. Sotalol
4. Bretylium
5. Amiodarone
261. How do the class III antiarrhyhthmic agents work?

What are the pros and cons to these agents?
These agents block K⁺ channels. When K⁺ channels are blocked, a smaller hyperpolarizing potassium current is generated. Therefore, K⁺ channel blockers cause a longer plateau and prolong repolarization.

Prolongation of the plateau duration increases the effective refractory period, which in turn decreases the incidence of re-entry. On the toxic side however, prolongation of the plateau duration increases the likelihood of developing early after depolarizations and torsades de pointes.
262. Ibutilide
MOA: Inhibits delayed rectifies K⁺ current. Blocks K⁺ channels, resulting in longer action potential plateau and prolonged repolarization

PURPOSE: Conversion of atrial fibrillation or atrial flutter to normal sinus rhythm

ADVERSE: AV block, bradycardia, sustained vtach; 2% develop torsades de pointes requiring electrical cardioversion

CONTRA: History of polymorphic ventricular tachycardia, such as torsades de pointes; pre-existing long QT syndrome
263. Three therapeutic notes for ibutilide...
1. Class IA and class III antiarrhythmic agents may increase potential for prolonged refractoriness

2. Drugs that prolong QT interval, i.e. antihistamines, phenothiazines, and TCAs, increase the risk of arrhythmia

3. Monitor QT interval during ibutilide administration
264. Dofetilide
MOA: Dofetilide inhibits exclusively the rapid component of the delayed rectifier K⁺ current and has no effect on the inward Na⁺ current. Blocks K⁺ channels, resulting in longer action potential plateau and prolonged repolarization in a dose-dependent manner

PURPOSE: Conversion of atrial fibrillation or atrial flutter to normal sinus rhythm; maintenance of normal sinus rhythm in pts with symptomatic atrial fibrillation or atrial flutter

ADVERSE: AV block, bradycardia, sustained vtach; 2% develop torsades de pointes requiring electrical cardioversion

CONTRA: Same as ibutilide. Additional contraindications include pts with creatinine clearance less than 20 mL/min

NOTES: Available orally only. Reduction in dosage in pts with renal dysfunction; *Reserved only for pts with highly symptomatic atrial fibrillation and/or atrial flutter*
265. Sotalol
MOA: Sotalol is a mixed class II and class III antiarrhythmic agent, which nonselectively antagonizes β-adrenergic receptors (via the L-isomer) and prolongs action potential duration by blocking K⁺ channels

PURPOSE: Life-threatening ventricular arrhythmias, maintenance of normal sinus rhythm in pts with symptomatic atrial fibrillation or flutter

ADVERSE: Bradycardia, torsades de pointes, PVCs, vfib, vtach, AV block, heart failure, bronchospasm; dyspnea, chest pain, fatigue

CONTRA: Severe sinus-node dysfunction, sinus bradycardia, second or third degree AV block; long QT syndrome; cardiogenic shock, uncontrolled heart failure, asthma
266. Therapeutic notes for sotalol
1. Sotalol is sued frequently in pts who cannot tolerate adverse effects of amiodarone

2. Use w/caution in pts with impaired renal function or diabetes mellitus

3. Avoid coadministration with ziprasidone and sparflocacin, which can prolong QT interval
267. Bretylium
MOA: Bretylium acts as both an antihypertensive agent and a class III antiarrhythmic agent. This drug is concentrated in the terminals of sympathetic neurons, causing initial release of norepinephrine but then inhibiting further release of norepinephrine. It also increases the action potential duration in normal and ischemic cardiac cells.

PURPOSE: Life-threatening ventricular arrhythmias

ADVERSE: Cardiac arrhythmia; marked hypotension, bradycardia, dizziness, anxiety, increased body temp

CONTRA: Digitalis-induced arrhythmias
268. How does amiodarone work?
Amiodarone is mainly a class III antiarrhythmic agent, but it also acts as a class I, class II, and class IV antiarrhythmic.

The ability of amiodarone to exert such a diversity of effects can be explained by its MOA: alteration of the lipid membrane in which ion channels and receptors are located.

In all cardiac tissues, amiodarone lengthens the refractory period by blocking the K⁺ channels responsible for repolarization; this prolongation of action potential duration decreases re-entry.
269. Amiodarone
MOA: Mainly a class III antiarrhythmic agent, but it also acts as a class I, class II, and class IV antiarrhythmic agent

PURPOSE: Recurrent ventricular fibrillation; unstable vtach, atrial fibrillation, supraventricular arrhythmias

ADVERSE: Arrhythmias, asystole, bradycardia, heart block, heart failure, hypotension, sinus arrest, neutropenia, pancytopenia, hepatic failure, severe pulmonary toxicity (pneumonitis, alveolitis, fibrosis), thyroid dysfunction; fatigue, corneal microdeposits, blue-gray skin pigmentation, photosensitivity

CONTRA: Pts receiving ritonavir, severe SA-node disease, second or third degree AV block; bradycardia with syncope
270. What are the major adverse effects of amiodarone particularly at high doses?
Cardiovascular: ↓ AV- or SA-node function; ↓ cardiac contractility

Pulmonary: Pneumonitis leading to pulmonary fibrosis

Thyroid: Hyperthyroidism or hypothyroidism

Hepatic: Elevated liver enzymes

Neurological: Peripheral neuropathy, headache, ataxia, tremors

Other: Corneal microdeposits; testicular dysfunction; skin discoloration
271. What are 7 therapeutic considerations for amiodarone?
1. IV formulation (Cordarone) contains benzyl alcohol, which has cause gasping respiration and cardiovascular collapse (gasping syndrome) in neonates
2. Pulmonary toxicity is more common at high doses
3. Coadministration of beta-blockers or calcium channel blockers may increase risk of sinus bradycardia, sinus arrest, and AV block
4. Coadministration of cholestyramine increases amiodarone elimination
5. Coadministration of cyclosporine, digoxin, flecainide, lidocaine, phenytoin, procainamide, quinidine, or theophylline may lead to increased levels of these drugs
6. Coadministration of drugs that prolong QT interval, such as disopyramide, thoridazine, phenothiazine, pimozide, quinidine, sparfloxacin, or TCAs may lead to prolonged QT interval and induces torsades de pointes
7. Coadministration of phenytoin may decrease amiodarone levels
272. What are the class IV antiarrhythmic agents?
Calcium channel blockers, such as verapil and diltiazem, which are more effective in cardiac tissues.

These agents are sued to treat re-entrant paroxysmal supraventricualr tachycardias, b/c these are often re-entrant arrhythmias that involves the AV node.
273. What is the major therapeutic action of the class IV antiarrhythmics?
The major therapeutic action of the class IV antiarrhythmics is to slow the action potential upstroke in AV nodal cells, leading to slowed conduction velocity thru the AV node.

This also blocks re-entrant arrhythmias in which the AV node is part of the re-entry circuit.
274. What are two other antiarrhythmic agents?
1. Adenosine
2. Ranolazine
275. Adenosine
MOA: Opens G protein-coupled K⁺ channel and suppresses calcium-dependent action potential, thereby inhibiting SA nodal, atrial, and AV nodal conduction

PURPOSE: Conversion of paroxysmal supraventricular tachycardia to normal sinus rhythm

ADVERSE: Facial flushing, bronchoconstriction in pts with asthma, chest pressure, diaphoresis, excessive SA or AV nodal inhibition

CONTRA: Second or third degree AV block; do not use adnosine for atrial fibrillation or atrial flutter

NOTES: Coadministration of carbamazepine may increase the degree of heart block; transient arrhythmia may occur at the onset of adenosine infusion
276. Ranolazine
MOA: May inhibit fatty-acid oxidation, delayed rectifier potassium current, or late sodium current

PURPOSE: Chronic angina pectoris

ADVERSE: Prolongs QT interval, syncope, acute renal dysfunction, constipation, dizziness, headache

CONTRA: Concurrent use of drugs that prolong QT interval; pre-existing long QT syndrome; concurrent use of moderately potent P450 3A inhibitors; hepatic dysfunction

NOTES: *Freq used in combination with beta blockers, amlodipine, or nitrates in pts who have not achieved adequate response w/other anti-anginal agents, *Avoid use in pts with severe renal impairment