Pathology_Robbins

Pathology_Robbins. Bacterialprostatitismaybeacuteorchronic;theresponsibleorganismusuallyisE. coli oranothergram-negativerod. Chronicpelvicpainsyndrome,despitesharedsymptomatologywithchronicbacterialprostatitis,isofunknownetiologyanddifficulttotreat. Granulomatousprostatitismaybeeitherinfectious(e.g.,followingtreatmentwithBCG)ornoninfectious. Benign prostatic hyperplasia (BPH) is an extremely common cause of prostatic enlargement resulting from proliferation of of stromal and glandular elements. It is present in a significant number of men by 40 years of age, and its frequency rises progressively thereafter, reaching 90% by the eighth decade of life. The enlargement of the prostate in men with BPH is an important cause of urinary obstruction.


Pathology_Robbins

Pathology_Robbins. Although the cause of BPH is incompletely understood, excessive androgen-dependent growth of stromal and glandular elements has a central role. BPH does not occur in males who are castrated before the onset of puberty or in males with genetic diseases that block androgen activity. Dihydrotestosterone (DHT), the ultimate mediator of prostatic growth, is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. DHT binds to nuclear androgen receptors, which regulate the expression of genes that support the growth and survival of prostatic epithelium and stromal cells. Although testosterone can also bind to androgen receptors and stimulate growth, DHT is 10 times more potent. MORPHOLOGYBPH virtually always occurs in the inner transition zone of the prostate. Theaffectedprostateisenlarged,typicallyweighingbetween60and100g,andcontainsmanywell-circumscribednodulesthatbulgefromthecutsurface( Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 18.11 ).Thenodulesmayappearsolidorcontaincysticspaces,thelattercorrespondingtodilatedglands.Theurethraisusuallycompressed,oftentoanarrowslit,bythehyperplasticnodules.Insomecases,hyperplasticglandularandstromalelementslyingjustundertheepitheliumoftheproximalprostaticurethraprojectintothebladderlumenasapedunculatedmass,producingaball-valvetypeofurethralobstruction. Microscopically,thehyperplasticnodulesarecomposedofvariableproportionsofproliferatingglandularelementsandfibromuscularstroma.Thehyperplasticglandsarelinedbytall,columnarepithelialcellsandaperipherallayerofflattenedbasalcells( Fig.18.12 ).Theglandularluminaoftencontainlaminatedproteinaceoussecretorymaterialknownascorporaamylacea. Because BPH preferentially involves the inner portions of the prostate, the most common manifestations are related to lower urinary tract obstruction, often in the form of difficulty in starting the stream of urine (hesitancy)


Pathology_Robbins


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Pathology_Robbins. and intermittent interruption of the urinary stream while voiding. These symptoms frequently are accompanied by urinary urgency, frequency, and nocturia, all indicative of bladder irritation. Clinical manifestations of prostatic hyperplasia occur in only about 10% of men with pathologic evidence of BPH. The presence of residual urine in the bladder due to chronic obstruction increases the risk for urinary tract infections. In some affected men, BPH leads to complete urinary obstruction, with resultant painful distention of the bladder and, in the absence of appropriate treatment, hydronephrosis (Chapter 14). Initial treatment is pharmacologic, using targeted therapeutic agents that inhibit the formation of DHT from testosterone (such as 5-alpha reductase inhibitors) or that relax prostatic smooth muscle by blocking α1-adrenergic receptors. Various surgical techniques are reserved for severely symptomatic cases that are recalcitrant to medical therapy.


Pathology_Robbins

Pathology_Robbins. BPHischaracterizedbyproliferationofbenignstromalandglandularelements.DHT,anandrogenderivedfromtestosterone,isthemajorhormonalstimulusforproliferation. BPHoriginatesintheperiurethraltransitionzone.Thehyper-plasticnodulesexhibitvariableproportionsofstromaandglands.Hyperplasticglandsarelinedbytwocelllayers,aninnercolumnarlayerandanouterlayercomposedofflattenedbasalcells. Clinicalfindingsresultfromurinarytractobstructionandincludehesitancy,urgency,nocturia,andpoorurinarystream.Chronicobstructionpredisposestorecurrenturinarytractinfections. Adenocarcinoma of the prostate and is the most common form of cancer in men, accounting for 27% of cancer cases in the United States in 2014. Its is uncommon before the age of 50 years. Over the past several decades, mortality from prostate cancer has decreased significantly, and it currently causes only 10% of cancer deaths in the United States.


Pathology_Robbins

Pathology_Robbins. The relatively low rate of mortality in men with prostate cancer is related in part to increased detection of the disease through screening (discussed later), but how effective screening is at saving lives is controversial. This seeming paradox is related to the wide variation in the natural history of prostate cancer, from aggressive and rapidly fatal to indolent disease of no clinical significance. Indeed, prostate carcinoma commonly is found incidentally at autopsy in men dying of other causes, and many more men die with prostate cancer than of prostate cancer. It is not currently possible to identify the tumors that will be “bad actors” with certainty; thus, while some men are no doubt saved by early detection and treatment of their prostate cancers, it is equally certain that others are being “cured” of clinically inconsequential tumors.


Pathology_Robbins

Pathology_Robbins. Clinical and experimental observations suggest that androgens, heredity, environmental factors, and acquired somatic mutations have roles in the pathogenesis and progression of prostate cancer.


Pathology_Robbins

Pathology_Robbins. • Androgens are of central importance. Cancer of the prostate does not develop in males who are castrated before puberty, indicating that androgens somehow provide the “soil,” the cellular context, within which prostate cancer develops. This dependence on androgens extends to established cancers, which often regress for a time in response to surgical or chemical castration. Notably, tumors that are resistant to anti-androgen therapy often acquire androgen receptor gene amplifications or mutations that permit androgen receptors to activate the expression of their target genes despite therapy. Thus, tumors that recur in the face of anti-androgen therapies still depend on gene products regulated by androgen receptors for their growth and survival. However, while prostate cancer, like normal prostate, is dependent on androgens for its survival, there is no evidence that androgens initiate carcinogenesis, nor are androgen levels associated with prostate cancer risk.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Heredity also contributes, as there is an increased risk among first-degree relatives of patients with prostate cancer. Prostate cancer is uncommon in Asians and its incidence is highest among African-Americans and in Scandinavian countries. Aggressive, clinically significant disease is more common in African-Americans than in Caucasians. Genome-wide association studies have identified a number of genetic variants that are associated with increased risk for developing prostate cancer. Although each variant carries only a small increased risk, the effect is multiplicative, such that men with multiple risk alleles may have up to a 5-fold increase in risk compared to the general population.


Pathology_Robbins

Pathology_Robbins. Environment also plays a role, as evidenced by the fact that in Japanese immigrants to the United States the incidence of the disease rises (although not to the level seen in native-born Americans). Also, as the diet in Asia becomes more westernized, the incidence of clinically significant prostate cancer in this region of the world is increasing. However, the relationship between specific dietary components and prostate cancer risk is unclear.


Pathology_Robbins

Pathology_Robbins. • Acquired genetic aberrations, as in other cancers, are the actual drivers of cellular transformation. Copy number variations in specific chromosomal regions and gene rearrangements are frequently seen in primary tumors. The most common gene rearrangements in prostate cancer create fusion genes consisting of the androgen-regulated promoter of the TMPRSS2 gene and the coding sequence of ETS family transcription factors. TMPRSS2-ETS fusion genes are found in approximately 40% to 60% of prostate cancers in Caucasian populations, and they occur relatively early in tumorigenesis. Notably, the prevalence of these rearrangements is lower among African-Americans and other ethnic groups. Other mutations commonly lead to activation of the PI3K/AKT signaling pathway (Chapter 6); of these, the most common are loss-of-function mutations involving the tumor suppressor PTEN, which acts as a brake on PI3K activity.


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Pathology_Robbins. Fig. 18.14 ).Somevariationinnuclearsizeandshapeisusual,butingeneral,pleomorphismisnotmarked.Mitoticfiguresareuncommon.Withincreasinggrade,irregularorraggedglandularstructures,cribriformglands,sheetsofcells,orinfiltratingindividualcellsarepresent.Inapproximately80%ofcases,prostatictissueremovedforcarcinomaalsoharborspresumptiveprecursorlesions,referredtoashigh-grade prostatic intraepithelial neoplasia (HGPIN). ManyofthemolecularchangesseenininvasivecancersarealsoseeninHPIN. Fig. 18.13 Adenocarcinomaoftheprostate.Carcinomatoustissueisseenontheposterioraspect(lower left). Notethesolidwhitertissueofcancer,incontrastwiththespongyappearanceofthebenignperipheralzoneonthecontralateralside.


Pathology_Robbins

Pathology_Robbins. In the United States, most prostate cancers are small, nonpalpable, asymptomatic lesions discovered on needle biopsy performed to investigate an elevated serum prostate-specific antigen (PSA) level (discussed later). Some 70% to 80% of prostate cancers arise in the outer (peripheral) glands, and a subset of these may be palpable as irregular hard nodules on digital rectal examination. A minority of carcinomas is discovered unexpectedly during histologic examination of prostate tissue removed by trans-urethral resection for BPH. Because of the peripheral location, prostate cancer is less likely than BPH to cause urethral obstruction in its initial stages. Locally advanced cancers often infiltrate the seminal vesicles and periurethral zones of the prostate and may invade the adjacent soft tissues, the wall of the urinary bladder, or (less commonly) the rectum. Bone metastases, particularly to the axial skeleton, are frequent late in the disease and typically cause osteoblastic


Pathology_Robbins

Pathology_Robbins. soft tissues, the wall of the urinary bladder, or (less commonly) the rectum. Bone metastases, particularly to the axial skeleton, are frequent late in the disease and typically cause osteoblastic (bone-producing) lesions that can be detected on http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 18.14 (A)Adenocarcinomaoftheprostatedemonstratingsmallglandscrowdedinbetweenlargerbenignglands.(B)Highermagnificationshowsseveralsmallmalignantglandswithenlargednuclei,prominentnucleoli,anddarkcytoplasm,ascomparedwiththelarger,benigngland(top). radionuclide bone scans.


Pathology_Robbins

Pathology_Robbins. The PSA assay is the most widely used test in the diagnosis and management of prostate cancer, but it suffers from a number of limitations. PSA is a product of prostatic epithelium and is normally secreted in the semen. Although PSA screening can detect prostate cancers early in their course, studies of the natural history of the disease (so-called “watch-and-wait studies”) have confirmed that many prostate cancers are clinically insignificant, requiring no treatment, sometimes for decades. Overtreatment of these indolent cancers can cause significant morbidity, particularly erectile dysfunction and incontinence. A second limitation of PSA as a biomarker is that it is not cancer-specific. BPH, prostatitis, prostatic infarcts, instrumentation of the prostate, and ejaculation all may increase serum PSA levels. Conversely, 20% to 40% of patients with organ-confined prostate cancer have PSA values below the cutoffs that are used to identify patients who are likely to have prostate cancer.


Pathology_Robbins

Pathology_Robbins. Because of these problems, PSA assays are being reappraised as screening tests. By contrast, once cancer is diagnosed, serial measurements of PSA are of great value in assessing the response to therapy. For example, a rising PSA level after radical prostatectomy or radiotherapy for localized disease is indicative of recurrent or disseminated disease.


Pathology_Robbins

Pathology_Robbins. The most common treatments for clinically localized prostate cancer are radical prostatectomy and radiotherapy. The prognosis after radical prostatectomy is based on the pathologic stage, whether the margins of the resected specimens are free of tumor, and Gleason grade. The Gleason grade, clinical stage, and serum PSA values are important predictors of outcome after radiotherapy. Because many prostate cancers follow an indolent course, active surveillance (“watchful waiting”) is an appropriate approach for older men, patients with significant comorbidity, or even some younger men with low serum PSA values and small, low-grade cancers. Advanced metastatic carcinoma is treated by androgen deprivation, either by orchiectomy or by administration of synthetic agonists of luteinizing hormone–releasing hormone (LHRH). In addition, there are many new therapies that reduce androgen synthesis or signaling in metastatic prostate cancer. Although anti-androgen therapy induces remissions,


Pathology_Robbins

Pathology_Robbins. hormone (LHRH). In addition, there are many new therapies that reduce androgen synthesis or signaling in metastatic prostate cancer. Although anti-androgen therapy induces remissions, androgen-independent clones almost invariably emerge, leading to rapid disease progression and death. As discussed earlier, these mutant clones commonly continue to express many genes that in normal prostate are androgen-dependent, suggesting that mechanisms arise to reactivate androgen signaling, even in the context of androgen deprivation therapy.


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Pathology_Robbins. SerumPSAmeasurementisacontroversialcancerscreeningtest,buthasclearvalueinmonitoringprogressiveorrecurrentprostatecancer. URETER,BLADDER,ANDURETHRA The renal pelves, ureters, bladder, and urethra are lined by specialized multi-layer transitional epithelium called urothelium. Beneath the mucosa are the lamina propria and, deeper yet, the muscularis propria (detrusor muscle), which makes up the bladder wall. Clinically significant disorders involving these organs include congenital aberrations, infectious and other inflammatory diseases, and neoplasms. http://ebooksmedicine.net Disorders of the ureter are uncommon and include congenital disorders, neoplasms, and reactive conditions. A few merit brief mention. Ureteropelvic junction (UPJ) obstruction, a congenital disorder, results in hydronephrosis. It usually manifests in infancy or childhood and is much more common in boys than in girls. It is the most frequent cause of hydronephrosis in infants and children.


Pathology_Robbins

Pathology_Robbins. Malignant tumors of the ureter are pathologically similar to those arising in the renal pelvis, calyces, and bladder (discussed later). Most are urothelial carcinomas. Retroperitoneal fibrosis is an uncommon cause of ureteral narrowing or obstruction characterized by a fibrous proliferative inflammatory process encasing the retro-peritoneal structures and causing hydronephrosis. The disorder occurs in middle to old age. At least a proportion of these cases occur in association with IgG4-related disease, characterized by fibroinflammatory lesions rich in IgG4-secreting plasma cells (Chapter 5). Other cases are associated with drug exposures (ergot derivatives, adrenergic blockers), radiation, infection, prior surgery, or malignant disease (lymphomas, urinary tract carcinomas). Most cases, however, have no obvious cause and are considered primary, or idiopathic (Ormond disease).


Pathology_Robbins

Pathology_Robbins. A bladder or vesical diverticulum consists of a pouchlike evagination of the bladder wall. Diverticula may be congenital but more commonly are acquired lesions that arise as a consequence of persistent urethral obstruction caused, for example, by benign prostatic hyperplasia. Although most diverticula are small and asymptomatic, they sometimes lead to urinary stasis predisposing to recurrent urinary tract infections and bladder stone formation. Cystitis takes many forms. Bacterial cystitis is common, particularly in women. The most common etiologic agents are coliform bacteria. Hemorrhagic cystitis may occur in patients receiving cytotoxic anti-tumor drugs, such as cyclophosphamide, and sometimes complicates adenovirus infection.


Pathology_Robbins

Pathology_Robbins. Hemorrhagic cystitis may occur in patients receiving cytotoxic anti-tumor drugs, such as cyclophosphamide, and sometimes complicates adenovirus infection. Interstitial cystitis causes a chronic pelvic pain syndrome, typically in women. It is characterized by suprapubic pain that increases with bladder filling and is relieved by bladder emptying, leading to very frequent urination during both day and night. Other symptoms include urgency, hematuria, and dysuria. Cystoscopic findings are nonspecific and include petechial hemorrhages. Up to 50% of patients have spontaneous remissions. Late in the course, transmural fibrosis may ensue, leading to a contracted bladder.


Pathology_Robbins

Pathology_Robbins. Malakoplakia is an uncommon inflammatory disease that most commonly occurs in the bladder. It results from defects in the phagocytic or degradative function of macrophages. As a result of this defect, undigested bacterial products accumulate within distended phagosomes, which are seen in histologic sections as abundant granular material within the cytoplasm of macrophages. The abnormal macrophages also contain laminated mineralized concretions known as Michaelis-Gutmann bodies, which result from deposition of calcium salts in the enlarged lysosomes. Polypoid cystitis is an inflammatory condition resulting from irritation to the bladder mucosa in which the urothelium is thrown into broad bulbous polypoid projections as a result of marked submucosal edema. Polypoid cystitis may be confused with papillary urothelial carcinoma both clinically and histologically.


Pathology_Robbins

Pathology_Robbins. Transitional epithelium lining the bladder may undergo various forms of metaplasia. Nests of urothelium (Brunn nests) sometimes grow downward into the lamina propria. Here, their central epithelial cells may variously differentiate into a cuboidal or columnar epithelium lining (cystitis glandularis); cystic spaces filled with clear fluid lined by flattened urothelium (cystitis cystica); or goblet cells resembling intestinal mucosa (intestinal metaplasia). As a response to injury, the urothelium often undergoes squamous metaplasia, which must be differentiated from normal glycogenated squamous epithelium, commonly found at the trigone in women.


Pathology_Robbins

Pathology_Robbins. Bladder cancer accounts for approximately 5% of cancers and 3% of cancer deaths in the United States. The vast majority of bladder cancers (95%–97% in the United States; 60%–90% in Africa) are urothelial carcinomas. Squamous cell carcinomas represent about 3% to 7% of bladder cancers in the United States but are much more common in countries such as Egypt, where urinary schistosomiasis is endemic. Adenocarcinomas of the bladder are rare. Carcinoma of the bladder is more common in men than in women, in industrialized than in developing nations, in urban than in rural dwellers, and in whites than in African-Americans. About 80% of patients are between 50 and 80 years of age.


Pathology_Robbins

Pathology_Robbins. Environmental factors are important in the pathogenesis of urothelial carcinoma and include cigarette smoking, various occupational carcinogens, and prior cyclophosphamide or radiation therapy. A family history of bladder cancer is a known risk factor. Squamous cell carcinoma is related to Schistosoma haematobium infections in areas where it is endemic. Cancers occurring in the setting of schistosoma infections arise in a background of chronic inflammation, which you will recall provides the “soil” for the development of a number of different cancers (Chapter 6).


Pathology_Robbins

Pathology_Robbins. Acquired genetic aberrations have been identified in urothelial carcinoma. Based on these observations, a model for bladder carcinogenesis has been proposed in which the tumor is initiated by deletions of tumor-suppressor genes on 9p and 9q, leading to the formation of superficial papillary tumors, which may then acquire TP53 mutations and progress to invasive disease. A second pathway, possibly initiated by TP53 mutations, leads first to carcinoma in situ and then, with loss of genes from chromosome 9, progresses to invasion. Additional genetic alterations in superficial tumors include mutations in telomerase, as well as mutations in fibroblast growth factor receptor 3 (FGFR3) and components of the RAS and PI3K/AKT pathways. Muscle invasive tumors often have mutations involving both TP53 and RB (Chapter 6). http://ebooksmedicine.net Fig.18.15 ).Themostcommonisanoninvasivepapillarytumor(


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig.18.15 ).Themostcommonisanoninvasivepapillarytumor( Fig.18.16 ).Theotherprecursoriscarcinomainsitu(CIS),whichisdiscussedlater.Inaboutone-halfofpatientswithinvasivebladdercancer,noprecursorlesionisfound;insuchcases,itispresumedthattheprecursorlesionwasovergrownbythehigh-gradeinvasivecomponent. Themostimportantprognosticfactorinnoninvasivepapillaryurothelialneoplasmsistheirgrade,whichisbasedonbotharchitecturalandcytologicfeatures.Asshownin Table18.2 ,thegradingsystemsubclassifiestumorsasfollows:(1)papilloma; (2)papillary urothelial neoplasm of low malignant potential (PUNLMP); (3)low-grade papillary urothelial carcinoma; and(4)high-grade papillary urothelial carcinoma Fig. 18.15 Morphologicpatternsofurothelialneoplasia. Table 18.2 Noninvasive Papillary Urothelial Neoplasms Fig. 18.16 Cystoscopicappearanceofapapillaryurothelialtumor,resem-blingcoral,withinthebladder.


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Pathology_Robbins. Table 18.2 Noninvasive Papillary Urothelial Neoplasms Fig. 18.16 Cystoscopicappearanceofapapillaryurothelialtumor,resem-blingcoral,withinthebladder. Fig.18.17 ).Theseexophyticpapillaryneoplasmsaretobedistinguishedfrominverted urothelial papilloma, whichisentirelybenignandnotassociatedwithanincreasedriskforsubsequentcarcinoma. CIS is defined by the presence of overtly malignant-appearing cells within a flat urothelium ( Fig.18.18 ).Likehigh-gradepapillaryurothelialcarcinoma,thetumorcellsinCISlackcohesivenessandareshedintotheurine,wheretheycanbedetectedbycytology.CIScommonlyismultifocalandsometimesinvolvesmostofthebladdersurfaceorextendsintotheuretersandurethra.Withouttreatment,50%to75%ofCIScasesprogresstoinvasivecancer.


Pathology_Robbins

Pathology_Robbins. Invasiveurothelialcancerassociatedwithpapillaryurothelialcancer(usuallyofhighgrade)orCISmaysuperficiallyinvadethelaminapropriaorextendmoredeeplyintounderlyingmuscle.The extent of invasion and spread (staging) at the time of initial diagnosis is the most important prognostic factor. Almostallinfiltratingurothelialcarcinomasarehighgrade. Squamouscellcarcinomasofthebladdertypicallyshowextensivekeratinizationandarenearlyalwaysassociatedwithchronicbladderirritationandinfection.Adenocarcinomasofthebladderarehistologicallyidenticaltoadenocarcinomasseeninthegastrointestinaltract.Somearisefromurachalremnantsinthedomeofthebladderorinassociationwithextensiveintestinalmetaplasia. HGUC, High-gradepapillaryurothelialcarcinoma;LGUC, low-gradepapillaryurothelialcarcinoma;PUNLMP, papillaryurothelialneoplasiaofuncertainmalignantpotential.*Rarecasesofprogressionhaveoccurredinimmunocompromisedpatients. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 18.17 Noninvasivelow-gradepapillaryurothelialcarcinoma.Highermagnification(right) showsslightlyirregularnucleiwithscatteredmitoticfigures(arrow).


Pathology_Robbins

Pathology_Robbins. Bladder tumors most commonly present with painless hematuria. Patients with urothelial tumors, whatever their grade, have a tendency to develop new tumors after excision, and recurrences may exhibit a higher grade. The risk for recurrence is related to several factors, including tumor size, stage, grade, multifocality, mitotic index, and associated dysplasia and/or CIS in the surrounding mucosa. Many recurrent tumors arise at sites different than that of the original lesion, yet share the same clonal abnormalities as those of the initial tumor; thus, these are true recurrences that stem from shedding and implantation of the original tumor cells at new sites. Whereas high-grade papillary urothelial carcinomas frequently are associated with either concurrent or subsequent invasive urothelial carcinoma, lower-grade papillary urothelial neoplasms often recur but infrequently invade (see Table 18.2 Fig. 18.18 Carcinomainsitu(CIS)withenlargedhyperchromaticnucleiandamitoticfigure(arrow).


Pathology_Robbins

Pathology_Robbins. Treatment of bladder cancer depends on tumor grade and stage and on whether the lesion is flat or papillary. For small, localized papillary tumors that are not high-grade, transurethral resection is both diagnostic and therapeutically sufficient. Patients with tumors that are at high risk for recurrence or progression typically receive topical immunotherapy consisting of intravesical instillation of an attenuated strain of the tuberculosis bacillus called Bacillus Calmette-Guérin (BCG), sometimes followed by intravesical chemotherapy. BCG elicits a granulomatous reaction that also triggers an effective local anti-tumor immune response. Patients are closely monitored for tumor recurrence with periodic cystoscopy and urine cytologic studies. Radical cystectomy is reserved for (1) tumor invading the muscularis propria; (2) CIS or high-grade papillary cancer refractory to BCG; and (3) CIS extending into the prostatic urethra and down the prostatic ducts, where BCG cannot come in contact


Pathology_Robbins

Pathology_Robbins. the muscularis propria; (2) CIS or high-grade papillary cancer refractory to BCG; and (3) CIS extending into the prostatic urethra and down the prostatic ducts, where BCG cannot come in contact the neoplastic cells. Advanced bladder cancer is treated using chemotherapy, which can palliate but is seldom curative.


Pathology_Robbins

Pathology_Robbins. Sexually transmitted diseases (STDs) have complicated human existence for centuries. Globally, approximately 15 million new cases of STD occur every year; of these, 4 million affect 15to 19-year-olds, and 6 million affect 20to 24-year-olds. Women are far more likely to become infected by an STD and to be asymptomatic. Of the 10 leading infectious diseases that require notification of the Centers for Disease Control and Prevention (CDC) in the United States, five—chlamydial infection, gonorrhea, acquired immunodeficiency syndrome (AIDS), syphilis, and hepatitis B—are STDs ( Table 18.3 ). In the United States, the two most common STDs are genital herpes and genital HPV infection, but these do not require CDC notification. http://ebooksmedicine.net HerpessimplexvirusPrimaryandrecurrentherpes,neonatalherpes HumanpapillomavirusCancerofpenis(somecases)Condylomaacuminatum,analcancer,Cervicaldysplasiaandcancer,vulvarcanceroropharyngealcarcinoma


Pathology_Robbins

Pathology_Robbins. HerpessimplexvirusPrimaryandrecurrentherpes,neonatalherpes HumanpapillomavirusCancerofpenis(somecases)Condylomaacuminatum,analcancer,Cervicaldysplasiaandcancer,vulvarcanceroropharyngealcarcinoma Chlamydia trachomatis Urethritis,epididymitis,LymphogranulomavenereumUrethralsyndrome,cervicitis,bartholinitis,proctitis salpingitis,andsequelae Trichomonas vaginalis Urethritis,balanitis Several of these entities, such as human immunodeficiency virus (HIV) infection, HPV infection, hepatitis B, and infection with E. histolytica, are discussed in other chapters.


Pathology_Robbins

Pathology_Robbins. Syphilis, or lues, is a chronic venereal infection caused by the spirochete Treponema pallidum. First recognized in epidemic form in 16th-century Europe as the Great Pox, syphilis is endemic in all parts of the world. In the United States, 20,000 cases of primary and secondary syphilis were reported to the CDC in 2014, representing almost a threefold increase since the year 2000. The increase for the most part can be attributed to the increased incidence in men who have sex with men. During 2013-2014, the incidence began to increase in women as well, raising the concern that there may be an impending increase in cases of congenital syphilis acquired from the mother. A strong racial disparity is evident; African Americans are affected six times more often than whites. Syphilis also is more common in HIV-infected patients, in whom syphilis is more likely to progress to organ involvement and neurosyphilis.


Pathology_Robbins

Pathology_Robbins. T. pallidum is a fastidious organism whose only natural host is man. The usual source of infection is contact with a cutaneous or mucosal lesion in a sexual partner in the early (primary or secondary) stages of syphilis. The organism is transmitted from such lesions during sexual activity through minute breaks in the skin or mucous membranes of the uninfected partner. In congenital cases, T. pallidum is transmitted across the placenta from mother to fetus, particularly during the early stages of maternal infection. Once introduced into the body, the organisms rapidly disseminate to distant sites through lymphatics and the blood, even before the appearance of lesions at the primary inoculation site. This widespread dissemination accounts for the protean manifestations of the disease ( Fig. 18.19 ), which in adults can be divided into primary, secondary, and tertiary stages.


Pathology_Robbins

Pathology_Robbins. Fig. 18.19 ), which in adults can be divided into primary, secondary, and tertiary stages. Primary syphilis. Several weeks after infection (mean, 21 days), a primary lesion, termed a chancre, appears at the point of spirochete entry. Systemic dissemination of organisms occurs during this period, while the host mounts an immune response. Two types of antibodies are formed: antibodies that cross-react with host constituents (nontreponemal antibodies) and antibodies to specific treponemal antigens. This humoral response, however, fails to eradicate the organisms.


Pathology_Robbins

Pathology_Robbins. Secondary syphilis. The chancre of primary syphilis resolves spontaneously over a period of 4 to 6 weeks and is followed in approximately 25% of untreated patients by the development of secondary syphilis. The manifestations of secondary syphilis, discussed in greater detail later, include generalized lymphadenopathy and mucocutaneous lesions. The mucocutaneous lesions of both primary and secondary syphilis are teeming with spirochetes and are highly infectious. Like the chancre, the lesions of secondary syphilis resolve even without antimicrobial therapy, at which point patients are said to be in early latent-phase syphilis.


Pathology_Robbins

Pathology_Robbins. Tertiary syphilis. Patients with untreated syphilis next enter an asymptomatic, late latent phase of the illness, defined as being more than 1 year after the initial infection. In about one third of cases, new symptoms develop over the next 5 to 20 years. This late symptomatic phase, or tertiary syphilis, is marked by the development of lesions in the cardiovascular system, central nervous system, or, less frequently, other organs. Spirochetes are much more difficult to demonstrate during the later http://ebooksmedicine.net Neurosyphilis: Meningovascular Tabes dorsalis General paresis Aortitis: Aneurysms Aortic regurgitation Gummas: Hepar lobatum Skin, bone, others Infantile: Childhood: Hutchinson teeth Eighth nerve deafness Fig. 18.19 Proteanmanifestationsofsyphilis. stages of disease, and patients are accordingly much less likely to be infectious than are those in the primary or secondary stages of disease.


Pathology_Robbins

Pathology_Robbins. Fig. 18.19 Proteanmanifestationsofsyphilis. stages of disease, and patients are accordingly much less likely to be infectious than are those in the primary or secondary stages of disease. T. pallidum also may be transmitted across the placenta from an infected mother to the fetus at any time during pregnancy, leading to the development of congenital syphilis. The likelihood of transmission is greatest during the early (primary and secondary) stages of disease, when spirochetes are most numerous. Because the manifestations of maternal disease may be subtle, routine serologic testing for syphilis is mandatory in all pregnancies. The stigmata of congenital syphilis typically do not develop until after the fourth month of pregnancy. In the absence of treatment, as many as 40% of infected infants die in utero, typically after the fourth month. The incidence of congenital syphilis is expected to rise because infection rates in women have increased in recent years.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThe pathognomonic microscopic lesion of syphilis is a proliferative endarteritis with an accompanying inflammatory infiltrate rich in plasma cells. Endarteritishasacentralroleintissueinjuryatallsitesinvolvedbysyphilis,butitspathogenesisisnotunderstood;thereisnoevidencethatthespirochetescauseanydamagetohosttissuesdirectly.Instead,itisthoughtthatthehostimmuneresponseisresponsiblefortheendothelialcellactivationandproliferationthatisthehallmarkoftheendarteritis,whicheventuallyleadstoperivascularfibrosisandluminalnarrowing.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Syphilis remains highly sensitive to antibiotics such as penicillin, a short course of which is sufficient to treat all stages of the disease. Serology is the mainstay of diagnosis. Serologic tests for syphilis include nontreponemal antibody tests and antitreponemal antibody tests. Nontreponemal tests measure antibody to cardiolipin, an antigen that is present in both host tissues and the treponemal cell wall. These antibodies are detected by the rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests. Nontreponemal antibody tests are usually positive by 4 to 6 weeks of infection and are strongly positive in the secondary phase of infection. However, nontreponemal antibody test results may revert to negative during the tertiary phase or, conversely, may on occasion be persistently positive in some patients after successful treatment. Two additional points regarding nontreponemal antibody tests deserve emphasis:


Pathology_Robbins

Pathology_Robbins. Nontreponemal antibody test results often are negative during the early stages of disease, even in the presence of a primary chancre. If there is a high degree of suspicion, these tests should be repeated in a few weeks. As many as 15% of positive VDRL test results are unrelated to syphilis. These false-positive results, which may be acute (transient) or chronic (persistent), increase in frequency with age and are associated with a variety of conditions, including the antiphospholipid antibody syndrome (Chapter 4).


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Pathology_Robbins. Treponemal antibody tests also become positive within 4 to 6 weeks after an infection but (unlike those for nontreponemal antibody tests) they usually remain positive indefinitely, even after successful treatment. Historically, treponemal antibody tests have been used to confirm the diagnosis of syphilis in those with a positive nontreponemal antibody test. However, thanks to recent test improvements, some centers have reversed this algorithm and now use treponemal antibody tests for screening and nontreponemal antibody tests to confirm the diagnosis. As with all serologic tests for infection, certain pitfalls must be considered when interpreting these tests, including the timing of the test relative to the infection (e.g., too early for an antibody response to have been mounted) and the confounding influence of altered immunity, particularly in those who are HIV-infected. http://ebooksmedicine.net SyphilisiscausedbyT. pallidum andhasthreestages.


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Pathology_Robbins. Thediagnosticmainstayisserologictesting.Nontreponemalantibodytests(VDRLandRPR)areusuallypositiveinearlydisease,butmaybenegativeinadvanceddisease.Treponemespecificantibodytestresultsbecomepositivelaterandremainpositiveindefinitely. Gonorrhea is a sexually transmitted infection caused by Neisseria gonorrhoeae. It is second only to chlamydial infection (discussed later) among reportable communicable diseases in the United States. With an estimated 350,000 cases reported in 2014, it remains a major public health problem. Coinfection with other STDs is common, particularly Chlamydia trachomatis, which is found in 30% of males with gonorrhea. The gravity of gonococcal infections has increased with the emergence of strains of N. gonorrhoeae that are resistant to multiple antibiotics.


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Pathology_Robbins. Humans are the only natural reservoir for N. gonorrhoeae. The organism is highly fastidious, and spread of infection requires direct contact with the mucosa of an infected individual, usually during sexual activity. The bacteria initially attach to mucosal epithelium, particularly of the columnar or transitional type, using a variety of membrane-associated adhesion molecules and structures termed pili (Chapter 9). Such attachment prevents the organism from being unceremoniously flushed away by body fluids such as urine or endocervical mucus. The organism then penetrates through the epithelial cells to invade the deeper tissues of the host. MORPHOLOGYN. gonorrhoeae provokesanintense,suppurativeinflammatoryreaction.Inmales,thismanifestsmostoftenasapurulenturethraldischarge,associatedwithanedematous,congestedurethralmeatus.Gram-negativediplococci,manywithinthecytoplasmofneutrophils,arereadilyidentifiedinGramstainsofthepurulentexudate(


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Pathology_Robbins. Fig.18.21 ).Ascendinginfectionmayresultinthedevelopmentofacuteprostatitis,epididymitis( Fig.18.22 ),ororchitis.Abscessesmaycomplicateseverecases.Urethralandendocervicalexudatestendtobelessconspicuousinfemales,althoughacuteinflammationofadjacentstructures,suchastheBartholinglands,isfairlycommon.Ascendinginfectioninvolvingtheuterus,fallopiantubes,andovariesresultsinacutesalpingitis,sometimescomplicatedbytuboovarianabscesses.Theacuteinflammatoryprocessisfollowedbythedevelopmentofgranulationtissueandscarring,withresultantstricturesandotherpermanentdeformitiesoftheinvolvedstructures,givingrisetopelvic inflammatory disease (Chapter19). Fig. 18.21 Neisseria gonorrhoeae. Gramstainofurethraldischargedemon-stratescharacteristicgram-negative,intracellulardiplococci(arrow). (Courtesy of Dr. Rita Gander, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)


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Pathology_Robbins. Fig. 18.22 Acuteepididymitiscausedbygonococcalinfection.Theepididy-misisinvolvedbyanabscess.Normaltestisisseenontheright. http://ebooksmedicine.net In most infected males, gonorrhea is manifested by the presence of dysuria, urinary frequency, and a mucopurulent urethral exudate within 2 to 14 days of the time of initial infection. However, urethral gonococcal infection can be detected in 40% of asymptomatic male contacts of women with symptomatic gonorrhea. Treatment with appropriate anti-microbial therapy results in eradication of the organism and prompt resolution of symptoms. Untreated infections may ascend to involve the prostate, seminal vesicles, epididymis, and testis. Neglected cases may be complicated by chronic urethral stricture and, in more advanced cases, by permanent sterility. Untreated men also may become chronic carriers of N. gonorrhoeae.


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Pathology_Robbins. Among female patients, acute infections acquired by vaginal intercourse may be asymptomatic or may be associated with dysuria, lower pelvic pain, and vaginal discharge. Untreated cases may be complicated by ascending infection, leading to acute inflammation of the fallopian tubes (salpingitis) and ovaries. Scarring of the fallopian tubes may occur, with resultant infertility and an increased risk for ectopic pregnancy. Gonococcal infection of the upper genital tract may spread to the peritoneal cavity, where the exudate may extend up the right paracolic gutter to the dome of the liver, resulting in gonococcal perihepatitis. Depending on sexual practices, other sites of primary infection in both males and females include the oropharynx and the anorectal area, with resultant acute pharyngitis and proctitis, respectively.


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Pathology_Robbins. Disseminated infection is much less common than local infection, occurring in 0.5% to 3% of cases of gonorrhea. It is more frequent in females than in males. Manifestations include, most commonly, tenosynovitis, arthritis, and pustular or hemorrhagic skin lesions. Endocarditis and meningitisarerarepresentations.Strainsthatcausedisseminated infection usually are resistant to the lytic action of complement, but rare patients with inherited complement deficiencies are susceptible to systemic spread regardless of the infecting strain. Gonococcal infection may be transmitted to infants during passage through the birth canal. The affected neonate may develop purulent infection of the eyes (ophthalmia neonatorum), an important cause of blindness in the past. The routine application of antibiotic ointment to the eyes of newborns has markedly reduced this disorder.


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Pathology_Robbins. Both culture and a variety of tests that detect organism-specific nucleic acids can be used to diagnose gonococcal infections. The advantage of culture is that it permits determination of antibiotic sensitivity. Nucleic acid–based tests are more rapid and somewhat more sensitive than culture, and are being used increasingly. GonorrheaisacommonSTDaffectingthegenitourinarytract.Controlofdisseminationrequiresaneffectivecomplement-mediatedimmuneresponse. Gonorrheapresentswithdysuriaandamilky,purulenturethraldischarge,althoughahighfrequencyofcasesareasymptomatic. About30%ofmenwithgonococcalurethritisalsoareinfectedwithC. trachomatis. Pregnantwomencantransmitgonorrheatonewbornsduringpassagethroughthebirthcanal. Diagnosiscanbemadebycultureoftheexudatesaswellasbynucleicacidamplificationtechniques.


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Pathology_Robbins. Pregnantwomencantransmitgonorrheatonewbornsduringpassagethroughthebirthcanal. Diagnosiscanbemadebycultureoftheexudatesaswellasbynucleicacidamplificationtechniques. Nongonococcal urethritis (NGU) and cervicitis are the most common forms of STD. A variety of organisms are implicated in the pathogenesis of NGU and cervicitis, including C. trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and Ureaplasma urealyticum. In the United States, most cases are apparently caused by C. trachomatis, and this organism is believed to be the most common bacterial cause of STD in the United States. Mycoplasma genitalium is a close second as a cause of NGU. The frequency of causative agents varies geographically and in certain patient populations such a men having sex with men. In almost 50% of the cases world wide no pathogen can be identified. As discussed earlier, gonorrhea infection frequently is accompanied by chlamydial infection.


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Pathology_Robbins. C. trachomatis is a small gram-negative bacterium that is an obligate intracellular pathogen. It exists in two forms. The infectious form, the elementary body, is capable of at least limited survival in the extracellular environment. The elementary body is taken up by host cells, primarily through a process of receptor-mediated endocytosis. Once inside the cell, the elementary body differentiates into a metabolically active form, termed the reticulate body. Using the energy sources of the host cell, the reticulate body replicates and ultimately forms new infectious elementary bodies, which have a tropism for columnar epithelial cells.


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Pathology_Robbins. C. trachomatis infections are associated with a wide range of clinical features that are virtually indistinguishable from those caused by N. gonorrhoeae. Clinically, patients typically present 1 to 5 weeks after exposure with dysuria with or without urethral discharge. Patients may develop epididymitis, prostatitis, pelvic inflammatory disease, pharyngitis, conjunctivitis, perihepatic inflammation, and, among individuals who engage in anal sex, proctitis. It is the most common cause of epididymitis in young men. Similar to gonococcus, a large percentage of both men and women are asymptomatic. C. trachomatis also causes lymphogranuloma venereum (LGV), discussed in the next section. The infection may be transmitted to newborns during vaginal birth, where up to 15% of exposed newborns develop chlamydial pneumonia and 50% develop chlamydial conjunctivitis.


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Pathology_Robbins. The morphologic and clinical features of chlamydial infection, with the exception of lymphogranuloma venereum, are virtually identical to those of gonorrhea. The primary infection is characterized by a watery to mucopurulent discharge that contains a predominance of neutrophils. Organisms are not visible in Gram-stained sections. In contrast with the gonococcus, C. trachomatis cannot be isolated with the use of conventional culture media. The diagnosis is best made by a nucleic acid amplification test on voided urine, which is now the gold standard. Another important manifestation of chlamydial infection is reactive arthritis (formerly known as Reiter syndrome), predominantly in patients who are HLA-B27 positive. This condition typically manifests as a combination of urethritis, conjunctivitis, arthritis, and generalized mucocutaneous lesions. http://ebooksmedicine.net •NGUandcervicitisarethemostcommonformsofSTD.MostcasesarecausedbyC. trachomatis, andtherestbyT. vaginalis,


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net •NGUandcervicitisarethemostcommonformsofSTD.MostcasesarecausedbyC. trachomatis, andtherestbyT. vaginalis, M. genitalium and U. urealyticum. C. trachomatis isagram-negativeintracellularbacteriumthatcausesadiseasethatisclinicallyindistinguishablefromgonorrheainbothmenandwomen.Diagnosiscanbemadebysensitivenucleicacidamplificationtestsinurinesamplesorvaginalswabs. InpatientswhoareHLA-B27positive,C. trachomatis infectioncancausereactivearthritisalongwithconjunctivitisandgeneralizedmucocutaneouslesions.


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Pathology_Robbins. InpatientswhoareHLA-B27positive,C. trachomatis infectioncancausereactivearthritisalongwithconjunctivitisandgeneralizedmucocutaneouslesions. LGV is a chronic, ulcerative disease caused by certain strains of C. trachomatis that are distinct from those causing the more common nongonococcal urethritis or cervicitis discussed earlier. It is endemic in parts of Asia, Africa, the Caribbean region, and South America. An increased incidence has been noted in the US in the past 15 years, due in large part of infections in men having sex with men, who are often co infected with HIV. As in the case of granuloma inguinale (discussed later), sporadic cases of LGV are seen most often among individuals with multiple sexual partners.


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Pathology_Robbins. Within 1 to 2 weeks of exposure, primary infection appears at the site of inoculation in the form of a genital ulcer or a mucosal inflammatory reaction. These primary lesions heal spontaneously, but the organisms at these sites seed draining lymph nodes, triggering a necrotizing lymphadenitis 2 to 6 weeks after the initial exposure. The lymphadenitis is usually unilateral and painful, and may lead to abscess formation. Abscesses sometimes rupture, spreading the inflammatory process into surrounding soft tissues. Rectal infections may progress to proctocolitis, associated with pain, constipation, fever, and bleeding, features that mimic inflammatory bowel disease. If untreated, rectal fissures and strictures may develop secondary to inflammation and fibrosis.


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Pathology_Robbins. The diagnosis of LGV is difficult because laboratory tests are not standardized and serologic tests have low specificity. As with other chlamydial infections, nucleic acid amplification tests have the highest sensitivity and specific and are becoming more widely available. Culture and serologic tests are less sensitive but are still used, particularly in areas where nucleic acid amplification tests are not available.


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Pathology_Robbins. Chancroid, sometimes called the “third” venereal disease (after syphilis and gonorrhea), is an acute, ulcerative infection caused by Haemophilus ducreyi, a small, gram-negative coccobacillus. The disease is most common in tropical and subtropical areas and is more prevalent in lower socioeconomic groups, particularly among men who have regular contact with prostitutes. Chancroid is one of the most common causes of genital ulcers in Africa and Southeast Asia, where it serves as an important cofactor in the transmission of HIV infection. Chancroid probably is underdiagnosed in the United States because most STD clinics do not have facilities for isolating H. ducreyi, and PCR-based tests are not widely available.


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Pathology_Robbins. The primary lesion of chanchroid appears within 4 to 7 days of inoculation. In male patients, the primary lesion is usually on the penis; in female patients, most lesions occur in the vagina or periurethral area. Over the course of several days, the surface of the primary lesion erodes to produce an irregular ulcer, which is more likely to be painful in males than in females. The regional lymph nodes, particularly in the inguinal region, become enlarged and tender in about 50% of cases within 1 to 2 weeks of the primary inoculation. In untreated cases, the inflamed and enlarged nodes (buboes) may erode the overlying skin to produce chronic, draining ulcers. A definitive diagnosis requires the identification of H. ducreyi on special culture media that are not widely available from commercial sources; even when such media are used, sensitivity is less than 80%. Therefore, the diagnosis often is based on clinical grounds alone. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Granuloma inguinale is a chronic inflammatory disease caused by Calymmatobacterium granulomatis, a minute, encapsulated coccobacillus related to the Klebsiella genus. This disease is uncommon in the United States and Western Europe, but it is endemic in the rural parts of certain tropical and subtropical regions. When it occurs in urban settings, transmission of C. granulomatis typically is associated with a history of multiple sexual partners. Untreated cases are characterized by extensive scarring, often associated with lymphatic obstruction and lymphedema (elephantiasis) of the external genitalia. Culture of the organism is difficult, and PCR-based assays are not widely available.


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Pathology_Robbins. T. vaginalis is a sexually transmitted protozoan that is a frequent cause of vaginitis. The trophozoite form adheres to the mucosa, where it causes superficial lesions. In females, T. vaginalis infection often is associated with loss of acid-producing lactobacilli. The incubation period is 4 to 28 days. It may be asymptomatic or be associated with pruritus and a profuse, frothy, yellow vaginal discharge. Urethral colonization may cause urinary frequency and dysuria. T. vaginalis infection typically is asymptomatic in males but in some cases may manifest as nongonococcal urethritis. The organism usually is demonstrable in smears of vaginal scrapings.


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Pathology_Robbins. Genital herpes infection, or herpes genitalis, is a very common STD. According to CDC, approximately 800,000 people get new infections every year in the United States. One in six persons between the ages of 14 and 49 has HSV-2 infection in the US. With increasing rate of HSV-1 infections the overall prevalence of genital herpes is likely much higher. Although both herpes simplex virus 1 (HSV-1) and HSV-2 can cause anogenital or oral infections, most cases of anogenital herpes are caused by HSV-2. However, recent years have seen a rise in the number of genital infections caused by HSV-1, in part due to the increasing practice of oral sex. Genital HSV infection may occur in any sexually active population. As with other STDs, the risk for infection is directly related to the number of sexual contacts. Up to 95% of HIV-positive men who have sex with men are seropositive for HSV-1 and/or HSV-2. HSV is transmitted when the virus comes into contact with a mucosal surface or broken skin of a


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Pathology_Robbins. contacts. Up to 95% of HIV-positive men who have sex with men are seropositive for HSV-1 and/or HSV-2. HSV is transmitted when the virus comes into contact with a mucosal surface or broken skin of a susceptible host. Such transmission requires direct contact with an infected individual, because the virus is readily inactivated at room temperature, particularly if dried.


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Pathology_Robbins. As discussed earlier, both HSV-1 and HSV-2 can cause genital or oral infection, and both produce indistinguishable primary or recurrent mucocutaneous lesions. Primary infection with HSV-2 often may be asymptomatic or may produce a variety of signs and symptoms. Locally painful vesicular lesions may be accompanied by dysuria, urethral discharge, local lymph node enlargement and tenderness, http://ebooksmedicine.net and systemic manifestations, such as fever, muscle aches, and headache. HSV is actively shed during this period, and shedding continues until the mucosal lesions have completely healed. However, asymptomatic viral shedding can occur as long as 3 months after diagnosis. Signs and symptoms may last for several weeks during the primary phase of disease. Recurrences are milder and of shorter duration than in the primary episode. Diagnosis is most often made by viral culture or nucleic acid amplification testing of fluid collected after “unroofing” of a vesicular lesion.


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Pathology_Robbins. In immunocompetent adults, herpes genitalis generally is not life-threatening. However, HSV poses a major threat to immunosuppressed patients, in whom fatal, disseminated disease may develop. Also life-threatening is neonatal herpes infection, which occurs in about one-half of infants delivered vaginally of mothers suffering from either primary or recurrent genital HSV infection. The viral infection is acquired during passage through the birth canal. Its incidence has risen in parallel with the rise in genital HSV infection. The manifestations of neonatal herpes vary from involvement of superficial sites (skin, eyes and mouth) to involvement of the CNS, with or without disseminated infection of other organs such as the liver and lungs. Approximately 60% of affected infants die of the disease, with significant morbidity occurring in about one-half of the survivors. PCR-based testing is far more sensitive and the preferred method for diagnosis of encephalitis.


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Pathology_Robbins. HPV causes a number of squamous proliferations in the genital tract, including condyloma acuminatum, as well as several precancerous lesions that commonly undergo transformation to carcinomas. The latter most commonly involve the cervix (Chapter 19), but also occur in the penis, vulva, oropharyngeal tonsil, and conjunctiva. Condylomata acuminata, also known as venereal warts, are caused by HPV types 6 and 11. These lesions occur on the penis as well as on the female genitalia. They should not be confused with the condylomata lata of secondary syphilis. Genital HPV infection may be transmitted to neonates during vaginal delivery. Recurrent and potentially life-threatening papillomas of the upper respiratory tract may develop subsequently in affected infants.


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Pathology_Robbins. Neonatalherpescanbelife-threateningandoccursinchildrenborntomotherswithgenitalherpes.Affectedinfantsmayhavegeneralizedherpes,oftenassociatedwithencephalitisandconsequenthighmortality. HPVcausesmanyproliferativelesionsofthegenitalmucosa,includingcondylomaacuminatum,precancerouslesions,andinvasivecancers. Barbieri CE, Tomlins SA: The prostate cancer genome: perspectives and potential, Urol Oncol 32:53.e15, 2014. [A review of molecular alterations in prostate cancer from recent sequencing data.] Boström PJ, Bjartell AS, Catto JW, et al: Genomic predictors of outcome in prostate cancer, Eur Urol 68:1033, 2015. [A recent review of biomarkers that are useful for clinical decision making in prostate cancer.] Bushman W: Etiology, epidemiology, and natural history of benign prostatic hyperplasia, Urol Clin North Am 36:403, 2009.


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Pathology_Robbins. Bushman W: Etiology, epidemiology, and natural history of benign prostatic hyperplasia, Urol Clin North Am 36:403, 2009. Cuzick J, Thorat MA, Andriole G, et al: Prevention and early detection of prostate cancer, Lancet Oncol 15:e484, 2014. [A review of the epidemiology and risk factors for prostate cancer as well as current screening methods and biomarkers.] Czerniak B, Dinney C, McConkey D: Origins of bladder cancer, Annu Rev Pathol 11:494, 2016. [Reviews recent advances in molecular characterization of bladder cancer.] Donovan B: Sexually transmitted infections other than HIV, Lancet 363:545, 2004. [A clinical review of STDs.] Epstein JI: An update of the Gleason grading system, J Urol 183:433, 2010. Fanfair RN, Workowski KA: Clinical update in sexually transmitted diseases—2014, Cleve Clin J Med 81:91, 2014. [A concise updated review with treatment recommendations.]


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Pathology_Robbins. Fanfair RN, Workowski KA: Clinical update in sexually transmitted diseases—2014, Cleve Clin J Med 81:91, 2014. [A concise updated review with treatment recommendations.] Hanna NH, Einhorn LH: Testicular cancer—discoveries and updates, N Engl J Med 371:2005, 2014. [A comprehensive review of current pathologic and clinical features of testicular germ cell tumors.] Le BV, Schaeffer AJ: Genitourinary pain syndromes, prostatitis and lower urinary tract symptoms, Urol Clin North Am 36:527, 2009. [A recent review of the etiology, diagnosis, symptoms, and treatment of prostatitis and interstitial cystitis along with pelvic pain syndromes.] Lee PK, Wilkins KB: Condyloma and other infections including human immunodeficiency virus, Surg Clin North Am 90:99, 2010.


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Pathology_Robbins. Lee PK, Wilkins KB: Condyloma and other infections including human immunodeficiency virus, Surg Clin North Am 90:99, 2010. Patel AK, Chapple CR: Medical management of lower urinary tract symptoms in men: current treatment and future approaches, Nat Clin Pract Urol 5:211, 2008. [This article clarifies the terminology used to evaluate men with lower urinary tract symptoms.] Rapley EA, Nathanson KL: Predisposition alleles for testicular germ cell tumour, Curr Opin Genet Dev 20:225, 2010. [An update on inherited risk factors in germ cell tumors.]. Spiess PE, Horenblas S, Pagliaro LC, et al: Current concepts in penile cancer, J Natl Compr Canc Netw 11:617, 2013. [A systematic review of the epidemiology and current treatment of penile cancers.] Sulak PJ: Sexually transmitted diseases, Semin Reprod Med 21:399, 2003. [An exhaustive review of STDs.] http://ebooksmedicine.net studentconsult.com Carcinoma of the Vulva Squamous Intraepithelial Lesion (SIL, Cervical


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Pathology_Robbins. Carcinoma of the Vulva Squamous Intraepithelial Lesion (SIL, Cervical Invasive Carcinoma of the Cervix Hydatidiform Mole: Complete and Partial Preeclampsia/Eclampsia (Toxemia of The vulva is the external female genitalia and includes the hair-bearing skin (labia majora) and mucosa (labia minora). Disorders of the vulva most frequently are inflammatory, rendering them more uncomfortable than serious. Malignant tumors of the vulva, although life-threatening, are rare. One of the most common causes of vulvitis is reactive inflammation in response to an exogenous stimulus, which may be an irritant (contact irritant dermatitis) or an allergen (contact allergic dermatitis). Scratching-induced trauma secondary to associated intense “itching” (pruritus) often exacerbates the primary condition.


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Pathology_Robbins. Contact irritant eczematous dermatitis manifests as well-defined erythematous weeping and crusting papules and plaques and may be a reaction to urine, soaps, detergents, antiseptics, deodorants, or alcohol. Allergic dermatitis has a similar clinical appearance and may result from allergy to perfumes; additives in creams, lotions, and soaps; chemical treatments on clothing; and other antigens.


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Pathology_Robbins. Vulvitis also may be caused by infections, which often are sexually transmitted. The most important infectious agents in North America are human papillomavirus (HPV), the causative agent of condyloma acuminatum, vulvar intraepithelial neoplasia (VIN), and one type of vulvar squamous carcinoma (discussed later); herpes simplex virus (HSV-1 or HSV-2), the agent of genital herpes; N. gonorrhoeae, a cause of suppurative infection of the vulvovaginal glands; and Treponema pallidum, which causes primary chancre at vulvar sites of inoculation. Candida also is a cause of vulvitis, but is not sexually transmitted. An important complication of vulvitis is obstruction of the excretory ducts of Bartholin glands. This blockage may result in painful dilation of the glands (Bartholin cyst) and abscess formation. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Lichen sclerosus is characterized by thinning of the epidermis, disappearance of rete pegs, a zone of acellular, homogenized, dermal fibrosis, and a bandlike mononuclear inflammatory cell infiltrate ( Fig. 19.1 ). It appears as smooth, white plaques (termed leukoplakia) or papules that in time may extend and coalesce. When the entire vulva is affected, the labia become atrophic and stiffened, and the vaginal orifice is constricted. Lichen sclerosus occurs in all age groups but most commonly affects postmenopausal women and prepubertal girls. The pathogenesis is uncertain, but the presence of activated T cells in the subepithelial inflammatory infiltrate and the increased frequency of autoimmune disorders in affected women suggest an autoimmune etiology. Lichen sclerosus is benign; however, 1% to 5% of women with symptomatic lichen sclerosus develop HPV negative squamous cell carcinoma of the vulva.


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Pathology_Robbins. Lichen simplex chronicus is marked by epithelial thickening (particularly of the stratum granulosum) and hyperkeratosis. Increased mitotic activity is seen in the basal and suprabasal layers; however, there is no epithelial atypia ( Fig. 19.1 ). Leukocytic infiltration of the dermis is sometimes pronounced. These nonspecific changes are a consequence of chronic irritation, often caused by pruritus related to an underlying inflammatory dermatosis. Lichen simplex chronicus appears as an area of leukoplakia. While no increased predisposition to cancer has been demonstrated when lesions are isolated, lichen simplex chronicus often is present at the margins of established vulvar cancer, suggesting some association with neoplastic disease.


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Pathology_Robbins. Lichen sclerosus and lichen simplex chronicus may coexist in different areas of the body in the same person, and both lesions may take the form of leukoplakia. Similar white patches or plaques also are seen in a variety of other benign dermatoses, such as psoriasis and lichen planus (Chapter 24), as well as in malignant lesions of the vulva, such as squamous cell carcinoma in situ and invasive squamous cell carcinoma. Thus, biopsy and microscopic examination are often needed to differentiate these clinically similar-appearing lesions. Lichensclerosusischaracterizedbyatrophicepithelium,sub-epithelialdermalfibrosis,andbandlikechronicinflammation. Lichensclerosuscarriesaslightlyincreasedriskfordevelopmentofsquamouscellcarcinoma. Lichensimplexchronicusischaracterizedbythickenedepithelium(hyperplasia),usuallywithadermalinflammatoryinfiltrate.


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Pathology_Robbins. Lichensclerosuscarriesaslightlyincreasedriskfordevelopmentofsquamouscellcarcinoma. Lichensimplexchronicusischaracterizedbythickenedepithelium(hyperplasia),usuallywithadermalinflammatoryinfiltrate. Thelesionsoflichensclerosusandlichensimplexchronicusmustbebiopsiedtodistinguishthemdefinitivelyfromothercausesofleukoplakia,suchassquamouscellcarcinomaofthevulva. Condyloma is the name given to any warty lesion of the vulva. Most such lesions can be assigned to one of two distinctive forms. Condylomata lata, not commonly seen today, are flat, minimally elevated lesions that occur in secondary syphilis (Chapter 18). The more common condylomata acuminata may be papillary and distinctly elevated or somewhat flat and rugose. They may occur anywhere on the anogenital surface, sometimes as single but more often as multiple lesions. When located on the vulva, they range from a few millimeters to many centimeters in diameter and are red-pink to pink-brown (


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Pathology_Robbins. Fig. 19.2 ). On histologic examination, the characteristic cellular feature is koilocytosis (a cytopathic change characterized by perinuclear cytoplasmic vacuolization and a wrinkled nuclear contour), a hallmark of HPV infection ( Fig. 19.2 ). Indeed, more than 90% of condylomata acuminata are positive for HPV subtypes 6 and 11. HPV is sexually transmitted, and identical lesions occur in men on the penis and around the anus in men and women. HPV 6 and 11 are low-risk viral types, and hence, vulvar condylomas do not commonly progress to cancer. However, women with condyloma acuminata are at risk of having other HPV-related lesions in the vagina and cervix. Fig.19.1Nonneoplasticvulvarepithelialdisorders.(A)Lichensclerosus.Thereismarkedthinningoftheepidermis,fibrosisofthesuperficialdermis,andchronicinflammatorycellsinthedeeperdermis.(B)Lichensimplexchronicusdisplayingthickenedepidermisandhyperkeratosis. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Fig.19.2(A)Numerouscondylomasofthevulva.(B)Histopathologicfeaturesofcondylomaacuminatumincludeacanthosis,hyperkeratosis,andcytoplasmicvacuolization(koilocytosis,center).(A, Courtesy of Dr.Alex Ferenczy, McGill University, Montreal, Quebec, Canada.) Carcinoma of the vulva represents about 3% of all female genital tract cancers, occurring mostly in women older than age 60. Approximately 90% of carcinomas are squamous cell carcinomas; most of the other tumors are adenocarcinomas or basal cell carcinomas.


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Pathology_Robbins. There appear to be two distinct forms of vulvar squamous cell carcinomas that differ in pathogenesis and course. The less common form is related to high-risk HPV strains (especially HPV type 16) and occurs in middle-aged women, particularly cigarette smokers. This form is often preceded by precancerous changes in the epithelium termed vulvar intraepithelial neoplasia (VIN). VIN progresses in many patients to greater degrees of atypia and eventually to carcinoma in situ; however, progression to invasive carcinoma is not inevitable and may occur only after many years. Environmental factors such as cigarette smoking and immunodeficiency appear to increase the risk of such progression.


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Pathology_Robbins. A second form of squamous carcinoma occurs in older women, sometimes following a long history of reactive epithelial changes, principally lichen sclerosus. It is preceded by a subtle lesion, differentiated vulvar intraepithelial neoplasia (dVIN), characterized by cytologic atypia confined to the basal layer and abnormal keratinization. If left untreated it may give rise to HPV negative, well-differentiated, keratinizing squamous cell carcinoma. MORPHOLOGYVINandearlyvulvarcarcinomascommonlymanifestasareasofleukoplakia.Inaboutone-fourthofthecases,thelesionsarepigmentedowingtothepresenceofmelanin.Withtime,theseareasaretransformedintoovertexophyticorulcerativeendophytictumors.HPV-positivetumorsareoftenmultifocalandwartyandtendtobepoorlydifferentiatedsquamouscellcarcinomas,whereasHPV-negativetumorsusuallyareunifocalandtypicallyarewell-differentiatedkeratinizingsquamouscellcarcinomas.


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Pathology_Robbins. Both forms of vulvar carcinoma tend to remain confined to their site of origin for a few years but ultimately invade and spread, usually first to regional lymph nodes. The risk of metastasis correlates with the depth of invasion. As with most carcinomas, outcome is dependent on tumor stage. The overall 5-year survival is 70% to 93% for patients with negative lymph nodes but decreases to 25% to 41% for patients with lymph node metastases. Paget disease is an intraepidermal proliferation of epithelial cells that can occur in the skin of the vulva or nipple of the breast (described later). However, unlike in the breast, where Paget disease is virtually always associated with an underlying carcinoma, only a minority of cases of vulvar (extramammary) Paget disease have an underlying tumor. Instead, vulvar Paget cells most commonly appear to arise from epidermal progenitor cells.


Pathology_Robbins

Pathology_Robbins. Paget disease manifests as a red, scaly, crusted plaque that may mimic the appearance of an inflammatory dermatitis. On histologic examination, large cells with abundant pale, finely granular cytoplasm and occasional cytoplasmic vacuoles infiltrate the epidermis, singly and in groups ( Fig. 19.3 ). The presence of mucin, as detected by periodic acid–Schiff (PAS) staining, is useful in distinguishing Paget disease from vulvar melanoma, which lacks mucin. http://ebooksmedicine.net Fig.19.3Pagetdiseaseofthevulva.Largetumorcellswithpale-pinkcyto-plasmareseeninfiltratingtheepidermis.Chronicinflammatorycellsarepresentintheunderlyingdermis. Intraepidermal Paget disease may persist for years or even decades without evidence of invasion. However, when there is an associated tumor involving skin appendages, the Paget cells may invade locally and ultimately metastasize. After metastasis occurs, the prognosis is poor.


Pathology_Robbins

Pathology_Robbins. HPV-relatedvulvarsquamouscellcarcinomasusuallyarepoorlydifferentiatedlesionsandsometimesaremultifocal.Theyoftenevolvefromvulvarintraepithelialneoplasia. Non–HPV-relatedvulvarsquamouscellcarcinomasoccurinolderwomenandusuallyarewelldifferentiatedandunifocal.Theyareoftenprecededby“differentiated”vulvarintraepithelialneoplasiaassociatedwithlichensclerosus. VulvarPagetdiseaseischaracterizedbyared,scalyplaquecausedbyproliferationofepithelialcellswithintheepidermis;usually,thereisnounderlyingcarcinoma,unlikePagetdiseaseofthenipple. In adult females, the vagina is seldom a site of primary disease. More often, it is involved secondarily by cancer or infections arising in adjacent organs (e.g., cervix, vulva, bladder, rectum).


Pathology_Robbins

Pathology_Robbins. In adult females, the vagina is seldom a site of primary disease. More often, it is involved secondarily by cancer or infections arising in adjacent organs (e.g., cervix, vulva, bladder, rectum). Congenital anomalies of the vagina fortunately are uncommon and include entities such as total absence of the vagina, a septate or double vagina (usually associated with a septate cervix and, sometimes, septate uterus), and congenital, lateral Gartner duct cysts arising from persistent wolffian duct rests.


Pathology_Robbins

Pathology_Robbins. Vaginitis is a common condition that is usually transient and of no clinical consequence. It is associated with the production of a vaginal discharge (leukorrhea). A large variety of organisms have been implicated, including bacteria, fungi, and parasites. Many are normal commensals that become pathogenic only in the setting of diabetes, systemic antibiotic therapy (which causes disruption of normal microbial flora), immunodeficiency, pregnancy, or recent abortion. In adults, primary gonorrheal infection of the vagina is uncommon. The other organisms worthy of mention, because they are frequent offenders, are Candida albicans and Trichomonas vaginalis. Candidal (monilial) vaginitis is characterized by a curdy white discharge. This organism is part of the normal vaginal flora in about 5% of women, so the appearance of symptomatic infection almost always involves one of the predisposing influences listed above or superinfection by a new, more aggressive strain. T. vaginalis is sexually


Pathology_Robbins

Pathology_Robbins. women, so the appearance of symptomatic infection almost always involves one of the predisposing influences listed above or superinfection by a new, more aggressive strain. T. vaginalis is sexually transmitted; it produces a watery, copious gray-green discharge in which parasites can be identified by microscopy. Trichomonas also can be identified in about 10% of asymptomatic women; thus, active infection usually stems from sexual transmission of a new strain.


Pathology_Robbins

Pathology_Robbins. Squamous cell carcinoma of the vagina is an extremely uncommon cancer that usually occurs in women older than 60 years in the setting of risk factors similar to those associated with carcinoma of the cervix (discussed later). Vaginal intraepithelial neoplasia (VAIN) is a precursor lesion that is nearly always associated with HPV infection. Invasive squamous cell carcinoma of the vagina is associated with the presence of HPV DNA in more than half of the cases, presumably derived from HPV-positive VAIN.


Pathology_Robbins

Pathology_Robbins. In 1970, clear cell adenocarcinoma, a very rare tumor, was identified in a cluster of young women whose mothers took diethylstilbestrol during pregnancy to prevent threatened abortion. Follow-up studies determined that the incidence of this tumor in persons exposed to diethylstilbestrol in utero is low (<1 per 1000, albeit about 40 times greater than in the unexposed population). In about one-third of exposed women, small glandular or microcystic inclusions develop in the vaginal mucosa. These lesions appear as red, granular foci lined by mucus-secreting or ciliated columnar cells. This condition is called vaginal adenosis and is benign but is important to recognize because it is from such precursor lesions that clear cell adenocarcinoma arises. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net SarcomaBotryoidesand children younger than 5 years of age, but may occur uncommonly in young women. It also may be found in Sarcoma botryoides (embryonal rhabdomyosarcoma) is other sites, such as the urinary bladder and bile ducts. a rare form of primary vaginal cancer that manifests as It is discussed further with other soft tissue tumors in soft polypoid masses. It usually is encountered in infants Chapter 21. Most cervical lesions are relatively banal inflammations (cervicitis), but the cervix also is the site of one of the most common cancers in women worldwide. Inflammatory conditions of the cervix are extremely common and may be associated with a purulent vaginal discharge. Cervicitis can be subclassified as infectious or noninfectious, although differentiation is difficult owing to the presence of normal vaginal flora including incidental vaginal aerobes and anaerobes, streptococci, staphylococci, enterococci, and Escherichia coli and Candida spp.


Pathology_Robbins

Pathology_Robbins. Much more important are Chlamydia trachomatis, Urea-plasma urealyticum, T. vaginalis, Neisseria gonorrhoeae, HSV-2 (the agent of herpes genitalis), and certain types of HPV, all of which are often sexually transmitted. C. trachomatis is by far the most common of these pathogens, accounting for as many as 40% of cases of cervicitis encountered in sexually transmitted infection clinics. Although less common, herpetic infections are noteworthy because maternal–infant transmission during childbirth may result in serious, sometimes fatal systemic herpetic infection in the newborn. Cervicitis commonly comes to attention on routine examination or because of leukorrhea. It often is treated empirically with antibiotics that are active against chlamydia and gonococcus. In some instances, nucleic acid amplification tests are used on vaginal fluid to identify the presence of these organisms as well as Trichomonas vaginalis.


Pathology_Robbins

Pathology_Robbins. Most tumors of the cervix are of epithelial origin and are caused by oncogenic strains of HPV. During development, the columnar mucus-secreting epithelium of the endocervix is joined to the squamous epithelial covering of the exocervix at the cervical os. With the onset of puberty, the squamocolumnar junction undergoes eversion, causing the columnar epithelium to become visible on the exocervix. The exposed columnar cells, however, eventually undergo squamous metaplasia, forming a region called the transformation zone, where tumors most commonly arise ( Fig. 19.4 HPV, the causative agent of cervical neoplasia, has a tropism for the immature squamous cells of the transformation zone. Most HPV infections are transient and are eliminated within months by the host immune response. A subset of infections persists, however, and some cause squamous intraepithelial lesions (SILs), which are precursors from which most invasive cervical carcinomas develop.


Pathology_Robbins

Pathology_Robbins. HPV is detectable by molecular methods in nearly all cases of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. Important risk factors for the development of CIN and invasive carcinoma thus are directly related to HPV exposure and include: Male partner with multiple previous sexual partners Persistent infection by high-risk strains of papillomavirus


Pathology_Robbins

Pathology_Robbins. Male partner with multiple previous sexual partners Persistent infection by high-risk strains of papillomavirus Like most other DNA viruses, HPV uses host cell DNA polymerases to replicate its genome and produce virions. Virions must be shed from the surface of the squamous mucosa, yet under normal circumstances squamous cell maturation is accompanied by a cessation of DNA replication, which would prevent virus production. HPV “solves” this problem through the action of two viral oncoproteins, E6 and E7. The E6 and E7 proteins of “high risk” HPV variants inhibit p53 and RB, respectively (Chapter 6), two potent tumor suppressors that act to suppress the division of squamous cells as they mature. E6 and E7 thus have a central role in the life cycle of HPV and largely explain the carcinogenic activity of HPV in the cervix and other sites that are prone to HPV infection (e.g., vulva, penis, oropharynx).


Pathology_Robbins

Pathology_Robbins. HPV variants are classified as high-risk or low-risk types based on their propensity to induce carcinogenesis. Fig.19.4Cervicaltransformationzoneshowingthetransitionfrommatureglycogenatedsquamousepithelium,toimmaturemetaplasticsquamouscells,tocolumnarendocervicalglandularepithelium. http://ebooksmedicine.net Low-risk HPV (6,11) (16, 18, others) hSIL (50,000/yr) Invasive cancer (13,000/yr) Metastasis (5000/yr) Persistent infection Viral integration Condyloma (hundreds of thousands/yr) SIL (~1 million/yr) Fig.19.5Possibleconsequencesofhumanpapillomavirus(HPV)infection.Progressionisassociatedwithintegrationofvirusandacquisitionofadditionalmutationsasdiscussedinthetext.SIL, Squamousintraepitheliallesion;hSIL, High-gradecervicalintraepitheliallesion.


Pathology_Robbins

Pathology_Robbins. High-risk HPV infection is the most important risk factor for the development of SIL that can progress to carcinoma. Two high-risk HPV viruses, types 16 and 18, account for approximately 70% of cases of SIL and cervical carcinoma. In general, infections with high-risk HPV types are more likely to persist, which is a risk factor for progression to carcinoma. These HPV types also show a propensity to integrate into the host cell genome, an event that is linked to progression. Low-risk HPV variants (e.g., types 6 and 11) associated with the development of condylomas of the lower genital tract ( Fig. 19.5), by contrast, express E6 and


Pathology_Robbins

Pathology_Robbins. E7 variants with different or weaker activities and do not integrate into the host genome, remaining instead as free episomal viral DNA. Despite the strong association of HPV infection with cancer of the cervix, HPV is not sufficient to drive the neoplastic process. As mentioned later, HPV-infected high-grade precursor lesions do not invariably progress to invasive cancer. Diverse other factors such as immune and hormonal status and coinfection with other sexually transmitted agents are suspected to play a role. Collectively these factors favor the acquisition of somatically acquired mutations that involve both oncogenes and tumor suppressor genes. Viral integration appear to contribute to transformation in two ways: 1) integration always disrupts an HPV gene that negatively regulates E6 and E7, which leads to their increased expression; and 2) sometimes HPV integrates near a host cell oncogene such as MYC, leading to its overexpression as well.


Pathology_Robbins

Pathology_Robbins. SquamousIntraepithelialLesion(SIL,CervicalIntraepithelialLesion) HPV-related carcinogenesis begins with the precancerous epithelial change termed SIL, which usually precedes the development of an overt cancer by many years, sometimes decades. In support of this idea, SIL peaks in incidence at about 30 years of age, whereas invasive carcinoma peaks at about 45 years of age. The classification of cervical precursor lesions has evolved with time. The current terminology is a two-tiered system that not only reflects the biology of the disease but also patient management, replacing a three-tiered system. SIL is divided into low-grade squamous intraepithelial lesion (LSIL), still often referred to as cervical intraepithelial neoplasia I (CIN I), and high-grade squamous intraepithelial lesion (HSIL), encompassing cervical intraepithelial neoplasia II and III (CIN II and III) of the previous three-tiered system.


Pathology_Robbins

Pathology_Robbins. LSIL is associated with productive HPV infection and does not progress directly to invasive carcinoma. Actually, most LSILs regress and only a small percentage progress to HSIL. HSIL demonstrates increased proliferation, arrested epithelial maturation, and lower levels of viral replication. LSIL is not treated as a premalignant lesion, whereas HSIL is considered at high risk for progression to carcinoma. Importantly, LSIL is 10 times more common than HSIL and while HSILs are precancerous, the majority of them fail to progress to cancer and may even regress. Patient management rests on the histopathologic diagnosis as discussed later. As shown in Table 19.1 , the decision to treat HSIL and to observe LSIL is based on differences in the natural histories of these two groups of lesions.


Pathology_Robbins

Pathology_Robbins. Cervical precancerous lesions are associated with abnormalities in cytologic preparations that can be detected long before any abnormality is visible on gross inspection. Early detection of SIL is the rationale for the Papanicolaou (Pap) test, in which cells are scraped from the transformation zone and examined microscopically. The Pap smear remains the most successful cancer-screening test ever developed. In the United States, Pap screening has dramatically lowered the incidence of invasive cervical tumors to about 13,000 cases annually with a mortality of about 4000 per year; in fact, cervical cancer no longer ranks among the top 10 causes of cancer deaths in U.S. women. Paradoxically, the incidence of SIL has increased to its present level of more than 50,000 cases annually. Increased detection has certainly contributed to this. The U.S. Food and Drug Administration has approved testing for HPV DNA in cervical scrapings. This test is highly sensitive but has lower


Pathology_Robbins

Pathology_Robbins. Table19.1NaturalHistoryofSquamousIntraepithelialLesions(SILs) HSIL(CINII,III)30%60%10%(tocarcinoma) aProgressionwithin10years.LSIL,Low-gradeSIL;HSIL,high-gradeSIL. http://ebooksmedicine.net Fig.19.6Spectrumofsquamousintraepitheliallesions(SIL)withnormalsquamousepitheliumforcomparison:LSILwithkoilocytoticatypia;HSILwithprogressiveatypiainalllayersoftheepithelium;andHSILwithdiffuseatypiaandlossofmaturation(carcinomainsitu,far right image). specificity than the Pap smear, and specific guidelines for its use have not been well established. One consideration is that while most women acquire HPV infections in their early 20s, these are usually cleared by the immune system and never progress to SIL, a process that occurs over many years. For this reason, HPV DNA screening is only recommended for women aged 30 or older, as a positive test at this age is more likely to identify an individual with a persistent infection that may lead to cervical neoplasia.


Pathology_Robbins

Pathology_Robbins. The quadrivalent HPV vaccine for types 6, 11, 16, and 18, and the more recently introduced 9-valent vaccine, are very effective in preventing HPV infections and are expected to greatly lower the frequency of genital warts and cervical cancers associated with these HPV genotypes. Despite its efficacy, vaccination does not supplant the need for routine cervical cancer screening—many at-risk women are already infected, and current vaccines protect against only some of the many oncogenic HPV genotypes.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.19.7 Fig.19.7Cytologicfeaturesofsquamousintraepitheliallesion(SIL)inaPapanicolaousmear.Superficialsquamouscellsmaystaineitherredorblue. (A)Normalexfoliatedsuperficialsquamousepithelialcells.(B)Low-gradesquamousintraepitheliallesion(LSIL).(CandD)Bothhigh-gradesquamousintraepitheliallesions(HSILs).Notethereductionincytoplasmandtheincreaseinthenucleus-to-cytoplasmratioasthegradeofthelesionincreases.Thisobservationreflectstheprogressivelossofcellulardifferentiationonthesurfaceofthecervicallesionsfromwhichthesecellsareexfoliated(see Fig.19.6). (Courtesy of Dr. Edmund S. Cibas, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig.19.6). (Courtesy of Dr. Edmund S. Cibas, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net SIL is asymptomatic and comes to clinical attention through an abnormal Pap smear result. These cases are followed up by colposcopy, in which acetic acid is used to highlight the lesions so they can be biopsied. Women with biopsy-documented LSIL are managed conservatively with careful observation, whereas HSILs and persistent LSIL are treated with surgical excision (cone biopsy). Follow-up smears and clinical examination are required in patients with HSIL, as these women remain at risk for HPV-associated cervical, vulvar, and vaginal cancers.


Pathology_Robbins

Pathology_Robbins. The most common cervical carcinomas are squamous cell carcinomas (75%), followed by adenocarcinomas and mixed adenosquamous carcinomas (20%) and small cell neuroendocrine carcinomas (<5%). All of these types of carcinomas are associated with HPV. Of interest, the relative proportion of adenocarcinomas has been increasing in recent decades owing to the decreasing incidence of invasive squamous carcinoma and suboptimal detection of glandular lesions by Pap smear.


Pathology_Robbins

Pathology_Robbins. Squamous cell carcinoma has a peak incidence at the age of about 45 years, some 10 to 15 years after detection of precursor SIL. As already discussed, progression of SIL to invasive carcinoma is variable and unpredictable and requires HPV infection as well as mutations in tumor suppressor genes and oncogenes. Risk factors for progression include cigarette smoking and human immunodeficiency virus (HIV) infection, the latter finding suggesting that immune surveillance plays a role in preventing progression. Although risk factors may help identify patients who are likely to progress from SIL to carcinoma, the only reliable way to monitor the disease course is with frequent physical examinations coupled with Pap smears and biopsy of suspicious lesions.


Pathology_Robbins

Pathology_Robbins. Fig.19.8Cervicaloswithsurrounding,invasive,exophyticcervicalcarcinoma. Invasive cervical cancer most often is seen in women who have never had a Pap smear or who have not been screened for many years. In such cases, cervical cancer often is symptomatic, with patients coming to medical attention for unexpected vaginal bleeding, leukorrhea, painful coitus (dyspareunia), or dysuria. The primary treatment is hysterectomy and lymph node dissection; small microinvasive carcinomas may be treated with cone biopsy. Radiation and chemotherapy are also of benefit in instances where surgery alone is not curative. Mortality is most strongly predicted by tumor stage and, in the case of neuroendocrine carcinomas (which pursue an aggressive course) to cell type.


Pathology_Robbins

Pathology_Robbins. Endocervical polyps are benign polypoid masses seen protruding from the endocervical mucosa (sometimes through the exocervix). They can be as large as a few centimeters and have a smooth, glistening surface with underlying cystically dilated spaces filled with mucinous secretions. The surface epithelium and lining of the underlying cysts are composed of the same mucus-secreting columnar cells that line the endocervical canal. The stroma is edematous and may contain scattered mononuclear cells. Superimposed chronic inflammation may lead to squamous metaplasia of the overlying epithelium and ulcerations. These lesions may bleed, thereby arousing concern, but they have no malignant potential. RiskfactorsforcervicalcarcinomaarerelatedtoHPVexposure,suchasearlyageatfirstintercourse,multiplesexualpartners,andotherfactorsincludingcigarettesmokingandimmunodeficiency.


Pathology_Robbins

Pathology_Robbins. ThePapsmearisahighlyeffectivescreeningtoolforthedetectionofSILandcarcinomaandhassignificantlyreducedtheincidenceofcervicalcarcinoma.HPVtestingiscurrentlybeingusedinconjunctionwiththePapsmear. The body (corpus) of the uterus is composed of the endometrium, consisting of glands and stroma, and the myometrium, made up of smooth muscle. The more frequent and significant disorders of the uterus are considered here. Inflammation of the endometrium is classified as acute or chronic depending on whether a neutrophilic or a lymphoplasmacytic infiltrate predominates, respectively. The diagnosis of chronic endometritis generally requires the presence of plasma cells, as lymphocytes are present even in the normal endometrium.


Pathology_Robbins

Pathology_Robbins. Endometritis is a component of pelvic inflammatory disease and is frequently a result of N. gonorrhoeae or C. trachomatis infection. Histologic examination shows a neutrophilic infiltrate in the superficial endometrium coexisting with a stromal lymphoplasmacytic infiltrate. Prominent lymphoid follicles may be seen, particularly in chlamydial infection. Tuberculosis causes granulomatous endometritis, frequently with associated tuberculous salpingitis and peritonitis. Although seen in the United States mainly in immunocompromised persons, tuberculous endometritis is common in countries in which tuberculosis is endemic, and it should be included in the differential diagnosis for pelvic inflammatory disease in women who have recently emigrated from endemic areas.


Pathology_Robbins

Pathology_Robbins. Endometritis also may be a result of retained products of conception subsequent to miscarriage or delivery or the presence of a foreign body such as an intrauterine device. Retained tissue or foreign bodies act as a nidus for ascending infection by vaginal or intestinal tract flora. Removal of the offending tissue or foreign body typically results in resolution. Clinically, all forms of endometritis manifest with fever, abdominal pain, and menstrual abnormalities. In addition, there is an increased risk of infertility and ectopic pregnancy due to damage and scarring of the fallopian tubes.


Pathology_Robbins

Pathology_Robbins. Adenomyosis refers to the presence of endometrial tissue in the myometrium. Nests of endometrial stroma, glands, or both are found deep in the myometrium interposed between the muscle bundles. This endometrial tissue induces reactive hypertrophy of the myometrium, resulting in an enlarged, globular uterus, often with a thickened uterine wall. Extensive adenomyosis may produce menorrhagia, dysmenorrhea, and pelvic pain, particularly just prior to menstruation, and can coexist with endometriosis.


Pathology_Robbins

Pathology_Robbins. Endometriosis is defined by the presence of endometrial glands and stroma in a location outside the uterus. It occurs in as many as 10% of women in their reproductive years and in nearly half of women with infertility. It frequently is multifocal and often involves pelvic structures (ovaries, pouch of Douglas, uterine ligaments, tubes, and rectovaginal septum). Less frequently, distant areas of the peritoneal cavity or periumbilical tissues are involved. Uncommonly, distant sites such as lymph nodes, lungs, and even heart, skeletal muscle, or bone are affected. Four hypotheses have been put forth to explain the origin of dispersed endometriotic lesions, all of which are viable: The regurgitation theory, which is currently favored, proposes that menstrual backflow through the fallopian tubes leads to implantation. The benign metastases theory holds that endometrial tissue from the uterus can “spread” to distant sites via blood vessels and lymphatics.


Pathology_Robbins

Pathology_Robbins. The benign metastases theory holds that endometrial tissue from the uterus can “spread” to distant sites via blood vessels and lymphatics. The metaplastic theory, on the other hand, posits endometrial differentiation of coelomic epithelium (mesothelium of pelvis and abdomen from which endometrium originates) as the source. The extrauterine stem/progenitor cell theory, proposes that circulating stem/progenitor cells from the bone marrow differentiate into endometrial tissue. Studies suggest that endometriotic tissue is not just misplaced but is also abnormal (


Pathology_Robbins

Pathology_Robbins. Studies suggest that endometriotic tissue is not just misplaced but is also abnormal ( Fig. 19.9 ). As compared to normal endometrium, endometriotic tissue exhibits increased levels of inflammatory mediators, particularly prostaglandin E2. It is proposed that the inflammation results from the recruitment and activation of macrophages by factors made by endometrial stromal cells. Stromal cells also make aromatase, leading to local production of estrogen. These factors enhance the survival and persistence of the endometriotic tissue within a foreign location (a key feature in the pathogenesis of endometriosis) and help to explain the beneficial effects of COX-2 inhibitors and aromatase inhibitors in the treatment of endometriosis. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig.19.9Proposedoriginsofendometriosis.Ovary Uterus Fallopian tube Endometriotic cysts Endometriotic implants Retrograde menstruation Activated macrophages Stromal proinflammatory factors PGE2 and other inflammatory mediators COX2 COX2 PGE2 MORPHOLOGYEndometriosistypicallyconsistsoffunctioningendometrium,whichundergoescyclicbleeding.Becausebloodcollectsintheseaberrantfoci,theyappeargrosslyasred-brownnodulesorimplants.Theyrangeinsizefrommicroscopicto1to2cmindiameterandlieonorjustundertheaffectedserosalsurface.Often,individuallesionscoalescetoformlargermasses.Whentheovariesareinvolved,thelesionsmayformlarge,blood-filledcyststhatturnbrown(chocolatecysts)asthebloodages( Fig. 19.10 ).Withseepageandorganizationoftheblood,widespreadfibrosisoccurs,leadingtoadhesionsamongpelvicstructures,sealingofthetubalfimbriatedends,anddistortionofthefallopiantubesandovaries.Thediagnosisdependsonfindingbothendometrialglandsandstromaatsitesexternaltotheendometrium.


Pathology_Robbins

Pathology_Robbins. Fig.19.10Ovarianendometriosis.Sectioningofovaryshowsalargeendo-metrioticcystwithdegeneratedblood(“chocolatecyst”). The clinical manifestations of endometriosis depend on the distribution of the lesions. Extensive scarring of the fallopian tubes and ovaries often produces discomfort in the lower abdomen and eventual sterility. Rectal wall involvement may produce pain on defecation, whereas involvement of the uterine or bladder serosa can cause dyspareunia (painful intercourse) and dysuria, respectively. Almost all cases feature severe dysmenorrhea and pelvic pain resulting from intrapelvic bleeding and intraabdominal adhesions.


Pathology_Robbins

Pathology_Robbins. Women commonly seek medical attention for abnormal uterine bleeding, such as menorrhagia (profuse or prolonged bleeding at the time of the period), metrorrhagia (irregular bleeding between the periods), or postmenopausal bleeding. Common causes include dysfunctional uterine bleeding, endometrial polyps, leiomyomas, endometrial hyperplasia, and endometrial carcinoma. The probable cause of uterine bleeding in any given case varies depending on the age of the patient ( Table 19.2 ). Abnormal bleeding from the uterus in the absence of an organic uterine lesion is called dysfunctional uterine bleeding. The most common cause of dysfunctional uterine bleeding is anovulation (failure to ovulate). Anovulatory cycles result from hormonal imbalances and are most common at menarche and in the perimenopausal period because of fluctuations in the hypothalamus/pituitary/ovarian axis. Less common causes of anovulation are